curriculum vitae prof. vincenzo pavone

Transcription

Prof. Vincenzo Pavone
CURRICULUM VITAE
PROF. VINCENZO PAVONE
Nome:
Vincenzo
Cognome:
Pavone
Luogo di nascita:
Napoli, Italia
Data di nascita:
29 gennaio 1952
Cittadinanza:
Italiana
Indirizzo di lavoro:
Dipartimento di Chimica “Paolo Corradini”
Università di Napoli “Federico II”
Complesso Universitario Monte S. Angelo
Via Cynthia, 46
80126 Napoli, Italia
Telefono:
+39-081674399
Fax:
+39-081674090
e-mail:
vincenzo.pavone@unina.it
1
CARRIERA UNIVERSITARIA
Settembre 1975 – dicembre 1975
Stage
pre-laurea
presso
l’Istituto
“G.
Donegani” della Montedison, Novara, Italia
Maggio 1976
Laurea in chimica (110/110 e lode)
Settembre 1977 – agosto 1978
Borsa di studio del CNR presso l’Istituto
Chimico dell’Università di Napoli
1978 – 1980
Visiting
Fellow
alla
“Section
of
Macromolecular Biology - Laboratory of
Chemical Biology - National Institute of
Arthritis,
Metabolism
and
Digestive
Diseases (NIAMDD) - National Institutes
of Health (NIH)”, Bethesda, MD, USA
Luglio 1980 – novembre 1987
Ricercatore universitario presso la Facoltà di
Scienze
MM.FF.NN.
dell’Università
di
Napoli “Federico II”
1987
Visiting
Fellow
alla
Mitsubishi–Kasei,
Institute of Life Science, Tokyo, Japan –
borsa di studio CNR-NATO
Novembre 1987 – novembre 1994
Professore Associato di Chimica Generale
presso la Facoltà di Scienze MM.FF.NN.
dell’Università di Napoli “Federico II”
2
Novembre 1994
Professore Ordinario di Chimica Generale
presso la Facoltà di Scienze MM.FF.NN.
dell’Università di Napoli “Federico II”
1997
Visiting Professor al “National Institute of
Bioscience and Human Technology, Agency
of Industrial Science and Technology”,
Tsukuba, Japan
3
ATTIVITA’ MANAGERIALI PIU’ RECENTI
2000-2002
Membro
del
Consiglio
amministrazione)
del
(con
Polo
funzioni
delle
di
Scienze
consiglio
e
di
Tecnologie
dell’Università di Napoli Federico II
Il Polo delle Scienze e Tecnologie è una divisione dell’Università di Napoli “Federico II” a
cui afferiscono i 38 Dipartimenti delle Facoltà di Scienze MM.FF.NN., Ingegneria e
Architettura.
1997-2002
Vice direttore del Dipartimento di Chimica “Paolo Corradini”
dell’Università di Napoli Federico II (Bilancio 2002: €
1.342.000,00)
2002-2008
Direttore del Dipartimento di Chimica “Paolo Corradini”
dell’Università di Napoli Federico II (Bilancio 2007: €
2.867.000,00)
Al Dipartimento di Chimica afferiscono 21 professori ordinari, 32 professori associati, 13
ricercatori, 9 assegnisti, 10 borsisti, 17 dottorandi di ricerca, 2 unità di personale di
biblioteca, 6 unità di personale tecnico, 8 unità di personale amministrativo. La nuova sede
del Complesso Universitario di Monte S.Angelo si estende su una superficie di circa 12.000
mq e consta di circa 30 laboratori di ricerca, 10 laboratori didattici e di un laboratorio di
didattica informatizzata.
2008-
Vice Presidente e membro del Consiglio di Amministrazione
della Società Consortile per Azioni BioTekNet (Capitale
Sociale: € 700.000,00)
4
La Società Consortile per Azioni BioTekNet di recente istituzione deriva dal Centro
Regionale di Competenza in Biotecnologie Industriali BioTekNet che è nato con l'obiettivo
di mettere a disposizione del mondo della produzione, con una logica di integrazione e
potenziamento, il rilevante patrimonio di competenze biotecnologiche esistente in regione
Campania. L'attività di BioTekNet è particolarmente focalizzata sullo sviluppo di processi
industriali e di tecnologie che utilizzano sistemi biologici o loro componenti, con particolare
riferimento a: nuove tecnologie fermentative; biosensori innovativi; biosistemi per la
depurazione delle acque; applicazioni biologiche avanzate per il settore alimentare;
enzimologia industriale. L’obiettivo strategico di BioTekNet è la creazione di una rete
integrata di competenze scientifiche, tecnologiche, strumentali ed economico-gestionali, allo
scopo di assicurare un efficace trasferimento del sapere al sistema industriale.
2007 a tutt’oggi
Membro del Consiglio di Amministrazione del Consorzio
Technapoli – Parco Scientifico e Tecnologico dell’Area
Metropolitana di Napoli e Caserta (Fondo consortile: €
1.625.855,00)
Il Consorzio Technapoli è il Parco Scientifico e Tecnologico (PST) dell’area metropolitana
di Napoli e di Caserta, il cui obiettivo strategico ed istituzionale è quello di incrementare la
competitività del sistema economico territoriale attraverso interventi volti a favorire la
ricerca e l’innovazione tecnologica, l’internazionalizzazione delle imprese e l’attrazione di
investimenti esteri.
Technapoli, per il raggiungimento del suo obiettivo strategico, coopera sia con i soggetti
economici locali (pubblici e privati) sia con network nazionali ed internazionali,
sviluppando attività di collegamento e di integrazione operativa tra Imprese, Università,
Pubblica Amministrazione e Centri di Ricerca pubblici e privati per la realizzazione di
progetti congiunti su tematiche connesse all’innovazione tecnologica.
5
Il Consorzio svolge un’ampia gamma di attività volte a sostenere e diffondere l’importanza
dell’innovazione tecnologica quale leva per acquisire vantaggi competitivi sul mercato
globale, sia in termini di sistema delle imprese che in termini più generali di “territorio”.
In particolare, Technapoli si è specializzato nella: erogazione di servizi telematici;
promozione e valorizzazione della tutela della proprietà intellettuale - Marchi e Brevetti;
redazione e gestione di progetti di ricerca, innovazione, formazione e trasferimento
tecnologico, nonché di piani di sviluppo industriale; promozione dell'aggregazione di imprese
che operano nello stesso settore industriale e/o in settori complementari.
1996-1998
Membro della comitato tecnico-scientifico del Consorzio ARPA
L’ARPA, Agenzia Ricerca e Produzione Avanzata dell'Università degli Studi di Napoli
Federico II, è una struttura di interfaccia tra domanda e offerta di servizi innovativi, in
particolare nell’ambito della ricerca, della consulenza e dell'alta formazione.
2004 a tutt’oggi
Membro della commissione spin-off dell’Università di Napoli
“Federico II”
2001 a tutt’oggi
Presidente della commissione di valutazione dei programmi di
scambi internazionali tra l’Università di Napoli “Federico II” ed
Università ed Istituti stranieri per la mobilità di breve durata di
docenti, studiosi e ricercatori
6
COORDINAMENTO E PARTECIPAZIONE A
PROGETTI DI RICERCA PIU’ RECENTI
1999-2000
PRIN-MIUR Anno 1998 - Prot. 9803184222;
∈ 145,000
Titolo: Metalloproteine e sistemi miniaturizzati: Struttura, attività e
applicazioni.
Abstract: Obiettivi principale di questo progetto è lo sviluppo di nuove
metalloproteine miniaturizzate, basate sulla autoagreggazione di
peptidi con ioni metallici, quali modello di ferritine e rubredossine.
Ruolo: Coordinatore nazionale, responsabile unità locale.
1999-2000
CNR - Biotechnology and Molecular Biology Program;
∈ 40,000
Titolo: Nuove esterasi/lipasi di interesse industriale e loro inibitori.
Abstract: Il progetto è rivolto ad uno studio delle relazioni strutturafunzione in nuove esterasi e/o lipasi, e di loro inibitori.
Ruolo: Co-investigatore
1999-2000
European Community FP4 Programme;
∈ 215,000
Titolo: Novel compounds that inhibit the activation of CD4-positive
T cells as immunosuppressive agents.
Abstract: Il progetto è rivolto alla sintesi di peptidi e peptido-mimetici,
corrispondenti ad un dominio discreto del complesso di maggiore
istocompatibilità (MHC) di classe II. Sulla base di calcoli teorici e di
preliminari
risultati
sperimentali,
queste
molecole
potrebbero
interferire con l’attivazione di cellule T – CD4 positive, attraverso un
7
nuovo meccanismo d’azione.
Ruolo: Responsabile unità locale
1999-2000
CNR – Progetto Coordinato Agenda 2000, codice -CNRC00781B_002;
∈ 10,000
Titolo: Metalloproteine, interazioni tra metalli e proteine, e loro
modelli.
Abstract: Il progetto di ricerca ha come obiettivo lo studio di nuove
metallo-proteine, dalla purificazione alla caratterizzazione strutturale
e funzionale. Parte integrante del progetto è lo sviluppo di metalloproteine in miniatura come mimetici di basso peso molecolare di
macromolecole complesse. Queste nuove molecole rappresentano
valide
alternative
per
applicazioni
industriali
dei
prodotti
biotecnologici di espressione.
Ruolo: PI
2001-2002
PRIN-MIUR Anno 2000 - prot. MM03185591;
∈ 120,000
Titolo: Metalloproteine e sistemi miniaturizzati: Struttura, attività e
applicazioni.
Abstract: Obiettivi principale di questo progetto è lo sviluppo di nuove
metalloproteine miniaturizzate basate sulla autoagreggazione di
peptidi con ioni metallici, che possono trovare svariate applicazioni,
quali ad esempio, catalizzatori, sensori o agenti detossificanti.
Ruolo: Coordinatore nazionale, responsabile unità locale
2002-2006
HPMD-CT-2001-00113 Marie Curie Fellowships;
€ 262,000
Titolo: Miniaturized metalloproteins: new biocatalysts by design.
8
Abstract: Il progetto è dedicato al reclutamento di ricercatori stranieri,
la cui attività è rivolta allo sviluppo di test catalitici, per la
caratterizzazione
funzionale
di
metalloproteine
in
miniatura
sviluppate nel gruppo di ricerca ospitante.
Ruolo: PI
2004-2005
PRIN-MIUR anno 2003 - prot. 2003037580; Paolo Maria Scrimin (PI);
€ 94,000
Titolo: Approccio supramolecolare a metalloproteine minimali.
Abstract: Scopo del progetto è lo sviluppo di sistemi catalitici
artificiali,
attraverso
un
approccio
supramolecolare.
Nuove
architetture molecolari complesse, in grado di coordinare ioni
metallici, rappresentano fattori chiavi nella realizzazione di processi
catalitici.
Ruolo: Responsabile Unità locale
2003-2007
FIRB-MIUR RBNE01RB9B; John Guardiola (PI);
€ 134,000
Titolo: Analisi comparata in vitro ed in vivo di vaccini ricombinanti
innovativi basati su sistemi procariotici di display, proteine di fusione
e peptidi bioattivi.
Abstract: Il progetto è rivolto allo sviluppo di nuovi vaccini, basati su
differenti sistemi, e ad una analisi comparativa delle loro proprietà
strutturali e funzionali.
2003-2007
FIRB-MIUR RBNE01LCKB; Giuseppe Scala (PI);
€ 200,000
Titolo: Identificazioni di peptidi e dominii proteici in grado di inibire
9
l'attività di geni coinvolti nella patogenesi di neoplasie delle cellule B
e del carcinoma del colon-retto.
Abstract: Il progetto è rivolto ad una migliore comprensione dei
meccanismi molecolari, che sono alla base delle trasformazioni
neoplastiche di cellule B e del carcinoma del colon. Ruolo dell’unità è
lo sviluppo di peptido-mimetici, disegnati ad hoc.
2005-2006
PRIN-MIUR anno 2004 - prot. 2004055484; Roberto Santucci (PI);
€ 65,000
Titolo: Ingegnerizzazione e caratterizzazione di metalloproteine in
soluzione ed immobilizzate su superfici.
Abstract: Il progetto è finalizzato a produrre varianti di citocromi c e
del citocromo P450, nonché di sistemi modello, allo scopo di ottenere
(i) una migliore comprensione dei meccanismi che controllano il
folding di metalloproteine, e (ii) una ottimizzazione del processo di
immobilizzazione di questi biosistemi su superfici solide o sol-gel,
mostrando i citocromi interessanti potenzialità d'impiego in area
biosensoristica.
Ruolo: Partecipante
2005
Legge Regionale N.5 - Annualità 2003;
€ 17,000
Titolo:. Modelli di metalloproteine contenenti siti ferro-ossigeno.
Abstract: Obiettivo principale del progetto è lo sviluppo di nuovi
composti (denominati DF: Due Ferri), basati su peptidi artificiali,
capaci di auto-assemblare in presenza di ioni metallici, per costituire
modelli di metalloproteine. In particolare, viene presa in esame la
classe di proteine ferro-ossigeno, allo scopo di costruire molecole in
10
grado di catalizzare reazioni di ossidazione, usando ossidanti "puliti",
quali ossigeno ed acqua ossigenata.
Ruolo: PI
2005 – 2006 FP6-2003-LIFESCIHEALTH-3 (STReP);
€ 200,000
Titolo: Identification of novel epitopes as HIV-1 vaccine candidates.
Abstract: Obiettivo finale del progetto è la selezione di epitopi
peptidici, in grado di mimare i domini dell’”envelope” del virus
dell’HIV-1. Essi sono interessanti candidati per lo sviluppo di vaccini.
Ruolo: Co-investigatore
2003-2008
Regione Campania – POR 2000-2006 - misura 3.16;
€ 750,000
Titolo: Biosensori Innovativi.
Abstract: Obiettivo del progetto è di sviluppare nuovi tipi di
biosensori elettrochimici e/o di fluorescenza, che consentano, con
tecnologie innovative, la determinazione di analiti di elevato interesse
in vari comparti, quali quello clinico, chimico- farmaceutico,
ambientale ed agro-alimentare. Ciò allo scopo di consentire una
integrazione sinergica tra ricerca sperimentale e richiesta industriale.
Ruolo: PI
2006-2009
MIUR 297/99;
€ 900,000
Titolo: Micro-sistema di diagnosi basato su biosensori elettrochimici
innovativi (MicroDiaSym).
Abstract: Obiettivo del presente progetto è la costruzione di un nuovo
sistema di diagnosi (in seguito indicato come MicroDiaSym), basato
11
su biosensori elettrochimici, in grado di rilevare analiti (quali ad
esempio sequenze di DNA, anticorpi, recettori) di elevato interesse
clinico, ambientale ed agro-alimentare.
Ruolo: PI
2007-2008
PRIN-MIUR Anno 2006- Prot. 2006039071; Paolo Maria Scrimin (PI);
€ 95,000
Titolo: Nanoproteine artificiali autoassemblate.
Abstract: Obiettivo del progetto è la preparazione e lo studio di
"nanoproteine
artificiali"
ottenute
mediante
un
processo
di
autoassemblaggio di tioli, funzionalizzati con peptidi, sulla superficie
di nanoparticelle di oro.
12
PRINCIPALI COLLABORAZIONI CON AZIENDE ITALIANE E
STRANIERE
1. Carlo Gavazzi Space – Sviluppo di un biosensore elettrochimico per uso
nelle navicelle spaziali.
La Carlo Gavazzi Space è una delle principali imprese europee di medie dimensioni
operante nella “space systems integration”, ed è parte di un cluster di imprese europee. La
Carlo Gavazzi Space è stata fondata nel 1981 ed il suo quartier generale ha sede a Milano.
La Società occupa fisici e ingegneri di alta qualificazione.
2. Sigma-Tau Research Switzerland – Sviluppo di nuovi agenti antitumorali.
La Sigma-Tau Research Switzerland si occupa della promozione, sviluppo, coordinamento e
prestazione di servizi attinenti le attività scientifiche, di ricerca di base, ricerca clinica,
sperimentazione, sviluppo e produzione, per conto proprio o di terzi, di processi fisici,
chimici, biologici e biotecnologici, di metodiche produttive e diagnostiche implicanti anche
l'ingegneria genetica, di prodotti biotecnologici, di molecole, di preparati per uso cosmetico o
farmaceutico, di prodotti intermedi o finiti destinati all'industria farmaceutica,
biotecnologica, chimica e cosmetica al consumatore finale.
3. Menarini Industrie Farmaceutiche Riunite – Sviluppo di nuovi antagonisti
della contrazione della muscolatura liscia.
E’ il primo gruppo farmaceutico italiano in Europa. L'attività di Ricerca del Gruppo
Menarini si svolge attraverso Menarini Ricerche, che si occupa di tutte le attività di
Ricerca e Sviluppo dalla fase di ideazione dei nuovi progetti fino alla fase di registrazione
del farmaco. Dall'acquisto del Centro di Ricerca Farmaceutica di Pomezia (Roma), nei
primi anni '80, nascono un modernissimo centro di biotecnologie, Menarini Biotech, e un
13
Centro per la Ricerca e Sviluppo in grado di offrire a Menarini ed alle sue collegate
un'organizzazione di ricerca razionale ed avanzata. Tutte queste iniziative contribuiranno
ad elevare il livello della qualità della ricerca Menarini, portandola al 9° posto nel mondo secondo un'indagine indipendente dell' “Institute for Scientific Information” di Philadelfia
- nel periodo che va dal 1981 al 1992. I programmi di ricerca, suddivisi nei centri di Firenze,
Pomezia, Lomagna, Pisa, Barcellona e Berlino, riguardano essenzialmente le patologie
cardiovascolari, l'oncologia e l'area dolore, infiammazione, asma con lo studio di antagonisti
recettoriali.
4. PRIMM - Membro del “Scientifc Advisory Board”.
La PRIMM è una SMI che offre servizi biotecnologici con sede e laboratori al San
Raffaele Biomedical Science Park di Milano. La Primm possiede anche una consolidata
esperienza in progetti R&D portati avanti in stretta collaborazione con importanti
istituzioni italiane e straniere. Uno dei principali focus aziendali è il disegno, la sintesi e lo
svilluppo di nuovi peptidi bioattivi per applicazioni terapeutiche. Le aree principali di
applicazione sono l’infiammazione, l’asma e le malattie infettive.
5. AXXAM – Consulente scientifico sul progetto “Fotoproteine”.
Axxam è una società privata con sede e laboratori al San Raffaele Biomedical Science Park
di Milano ed è uno spin-off della Bayer HealthCare, Research and Development
Organization. Nel 2006 ha inaugurato i laboratori al Polaris, il parco Scientifico e
Tecnologico della Sardegna. Axxam ha un team di più di 60 unità di personale altamente
qualificato. Il programma interno delle ricerche si sviluppa su due filoni principali: 1)
Nuove piattaforme tecnologiche basate sulla Photina®, una nuova fotoproteina attivata dal
Ca2+; 2) sviluppo di piattaforme per l’identificazione di nuovi target in particolari settori
terapeutici come il dolore e l’osteoporosi.
14
6. Norsk Hydro - Consulente scientifico del progetto “Cancer Vaccine”.
La Norsk Hydro è una compagnia con una forte presenza dello Stato norvegese
prevalentemente incentrata sulla produzione petrolifera, quella dell'alluminio e dei
fertilizzanti. L'azienda è il secondo più grande operatore del gas e del petrolio sulla
piattaforma continentale norvegese ed è una grande azienda integrata dell'alluminio, quarta
nel mondo. Nel 1999 la Norsk Hydro ha acquistato un'altra azienda norvegese del gas e del
petrolio, “Petrolio Saga” e nel 2002 la Norsk Hydro ha acquistato il produttore tedesco
principale dell'alluminio. Ha anche acquisito dal gruppo Eni tutta la produzione di
fertilizzanti in Italia acquisendo un ruolo dominante in Europa. La Norsk Hydro ha
impianti in circa 40 paesi intorno al mondo ed è attiva su tutti i continenti. Lo stato
norvegese dichiara di possedere la proprietà di 43.8 per cento dell'azienda. Il numero dei
dipendenti è 36.000. La Norsk Hydro ha una divisione Biotech che ha dato origine ad una
serie di spin-off aziendali su prodotti biotech specifici. Il progetto “Cancer Vaccine” è stato
incorporato nella società GEMVAX.
15
COLLABORAZIONI INTERNAZIONALI DOCUMENTATE DA
LAVORI IN COLLABORAZIONE
Svizzera:
1.
Altmann Eva
Novartis Institutes for BioMedical Research, CH4002 Basel;
2.
Lorenzi Gian Paolo
Technische-Chemische
Laboratorium,
ETH
-
Zentrum 8092, Zurich;
3.
Mutter Manfred
Institute of Molecular and Biological ChemistryEcole Polytechnique Fédérale de Lausanne, 1015
Lausanne;
USA:
4.
Mapelli Claudio
Oncology and Peptide Research, Bristol-Myers
Squibb
Pharmaceutical
Research
Institute,
Lawrenceville;
5.
DeGrado William F.
Department of Biochemistry and Biophysics,
School of Medicine, University of Pennsylvania,
Philadelphia, PA;
6.
Di Costanzo Luigi
Roy and Diana Vagelos Laboratories, Department
of
Chemistry,
University
of
Pennsylvania,
Philadelphia, Pennsylvania;
7.
Schechter Alan N.
Molecular Medicine Branch, National Institute of
Diabetes and Digestive and Kidney Diseases, NIH,
Bethesda, MD;
8.
Luskey Kenneth L.
Department
of
Molecular
Genetics
and
Department of Internal Medicine University of
Texas
Health
Science
Center
at
Dallas
Southwestern Medical School, Dallas, Texas;
16
9.
Dutton Leslie P.
Johnson Research Foundation, Department of
Biochemistry
and
Biophysics,
University
of
Pennsylvania, Philadelphia, Pennsylvania;
10. Goodman Murray
Department of Chemistry and Biochemistry,
University of California, San Diego, La Jolla, CA;
11.
Felix Arthur
School of Theoretical and Applied Science,
Ramapo College of New Jersey, Mahwah, NJ;
12. Lahr Stephen
Department of Protein Design, Centocor, Radnor,
PA;
13. Mierke Dale F.
Department of Chemistry, Dartmouth College,
Hanover, NH;
14. Summa Christopher M. Department
of
Structural
Biology,
Stanford
University School of Medicine, Stanford, CA;
15. Giovanna Ghirlanda
Department of Chemistry and Biochemistry,
Arizona State University, Tempe, Arizona;
Norvegia:
16. Ericsen Jon Amund
GemVax AS, Oslo;
17. Naess Hilde Merete
Pronova Biopharma;
Giappone:
18. Nagai Ukon
Mitsubishi Kasei Institute of Life Sciences, Tokyo;
19. Yamada Takashi
Department of Chemistry, Faculty of Science,
Konan University, Kobe;
20. Miyazawa Toshifumi
Frontier Institute for Biomolecular Engineering
Research (FIBER), Konan University, Okamoto,
Higashinada-ku, Kobe;
Francia:
21. Chottard Genevieve
Laboratoire de Chimie Inorganique et Matériaux
Moléculaires, ESA CNRS 7071, Université Pierre
17
et Marie Curie, Paris;.
22. Mansuy Daniel
Laboratoire
de
Chimie
et
Biochimie
Pharmacologiques et Toxicologiques, CNRS UMR
8601, Université Paris Descartes, 45 Rue des Saints
Pères, Paris;
Inghilterra:
23. Fraternali Franca
Randall Division of Cell and Molecular Biophysics,
King's College London, London;
Polonia:
24. Leplawy Miroslaw T.
Institute of Organic Chemistry, Technical
University of ód , eromskiego 116, 90-924 ód ;
India:
25. Kishore Raghuvansh
Institute of Microbial Technology, Sector 39-A,
Chandigarh;
Germania:
26. Wieland Theodor
Max-Planck-Institut ffir Medizinische Forschung,
Jahnstrasse 29, D-6900 Heidelberg
18
RICERCATORI STRANIERI CHE HANNO LAVORATO A
NAPOLI SOTTO LA GUIDA DEL PROF. VINCENZO PAVONE
1.
Wonnemann Jörg
Organisch-Chemisches
Institut
Westfälische
Wilhelms-Universität, Corrensstrasse 40, 48149
Münster, Germany.
2.
Hengelen Mirelle
Leiden
Institute
of
Chemistry,
Gorlaeus
Laboraties, Leiden University, 2300 RA Leiden,
The Netherlands.
3.
Lataika Rafal
Wroclaw University of Technology, Institute of
Organic
Chemistry,
Biochemistry
and
Biotechnology, Wybrzeze Wyspianskiego, 27 50370 WROCLAW, Poland.
4.
Torres Rafael
School
of
Chemistry,
The
University
of
Edinburgh, West Mains Road, Edinburgh EH9 3JJ,
Scotland.
5.
Tepper Armand
Leiden
Institute
of
Chemistry,
Gorlaeus
Laboratories, Leiden University, Einsteinweg 55,
2333 CC Leiden, The Netherlands.
19
SOMMARIO DELLA PRODUZIONE SCIENTIFICA
• Totale delle review: n. 12.
Review più significative:
1. Chemical Reviews (2001), 101(10), 3165-3189.
2. Annual Review of Biochemistry (1999), 68, 779-819.
3. Biological Chemistry (1998), 379(8/9), 987-1006.
• Totale dei lavori pubblicati su riviste ad alta diffusione: n. 142.
Lavori più significativi:
1. Nature Structural Biology (2001), 8(7), 611-615.
2. PNAS USA (2003), 100(7), 3772-3777.
3. PNAS USA (2000), 97(12), 6298-6305.
4. PNAS USA (2000), 97(22), 11922-11927.
5. PNAS USA (1992), 89(15), 7218-21.
6. PNAS USA (1986), 83(7), 1988-92.
7. PNAS USA (1982), 79(24), 7951-4.
8. Angewandte Chemie, International Edition (2003), 42(4), 417-420.
10. Journal of Molecular Biology (1990), 214(3), 633-5.
11. Journal of the American Chemical Society (2001), 123(51), 12749-12757.
20
20. Journal of Pharmacology and Experimental Therapeutics (1994), 271(3),
1489-500.
21. Journal of Biological Chemistry (1983), 258(23), 14725-32.
22. Journal of Biological Chemistry (1981), 256(17), 9229-34.
23. Protein Science (1999), 8(1), 91-95.
24. Protein Science (1998), 7(2), 243-253.
25. Journal of Medicinal Chemistry (1996), 39(10), 2008-17.
• Totale dei brevetti: n. 7
Brevetti internazionali:
1. WO2008017372
2. WO2004065406
3. WO2002012278
4. WO2000027880
5. WO9731941
6. WO9321227
• Totale dei proceedings: n. 33
21
SOMMARIO DELLE ATTIVITA’
Il prof. Pavone, laureato con lode in chimica all’università di Napoli, ha iniziato la
sua carriera nel 1976 ed ha avuto numerose esperienze formative all’estero (USA e
Giappone) e presso Aziende (Montedison e Mitsubishi). La sua produzione
scientifica è stata particolarmente intensa e negli ultimi 10 anni il prof. Pavone ha
assunto incarichi di responsabilità via via crescenti. In particolare la direzione del
Dipartimento di chimica, che per dimensione e tipologia organizzativa e
gestionale corrisponde alla direzione di in Istituto CNR di medio-grandi
dimensioni, è stata caratterizzata da un particolare impegno che ha consentito il
raggiungimento di significativi obiettivi, come la buona produzione scientifica
dell’intero dipartimento ed un raddoppio delle entrate finalizzate alla ricerca.
Questo impegno ha, tuttavia, prodotto un rallentamento della sua produzione
scientifica non potendo contare su un gruppo di ricerca di dimensioni adeguate.
Ciononostante, i risultati scientifici accumulati in questi ultimi anni saranno
presto oggetto di numerose ed importanti pubblicazioni.
Il prof. Pavone è stato ed è particolarmente attento alle potenzialità applicative
delle sue ricerche, come testimoniato dai brevetti internazionali depositati e di cui
è inventore. Questo aspetto ha consentito al prof. Pavone di intrattenere numerose
collaborazioni con gruppi industriali italiani e stranieri.
Le ricerche del prof. Pavone sono motivo di attrazione a livello internazionale,
come testimoniato anche dai ricercatori stranieri che hanno voluto unirsi al suo
gruppo. La dimensione internazionale è anche testimoniata da importanti review
su invito (Chemical Reviews e Annual Review of Biochemistry).
Il prof. Pavone ha anche una buona capacità attrattiva di risorse economiche.
Negli ultimi 10 anni ha potuto contare su finanziamenti pubblici per circa
3.000.000 di euro e circa 500.000 euro da soggetti privati. Le sue ricerche sono state
in parte anche finanziate dal CNR. Il prof. Pavone intrattiene anche numerose
collaborazioni con altri Istituti del CNR.
22
ATTIVITÀ SCIENTIFICA
L’attività scientifica del Prof. Vincenzo Pavone è iniziata nel 1976 e si è sviluppata
secondo linee di ricerca di grande attualità. Le principali tematiche di ricerca sono
di seguito elencate:
1. METALLO-PROTEINE ARTIFICIALI
FERRO-PROTEINE NON-EME (2000 a tutt’oggi)
EMOPROTEINE (1997 a tutt’oggi)
PROTEINE FERRO-ZOLFO (1995 - 2002)
2. PROTEINE
UPAR (2006 a tutt’oggi)
RANTES (2000 a tutt’oggi)
TROMBINA (1996 - 1999)
STRUTTURA SECONDARIA DELLE PROTEINE (1985 - 1996)
COMPOSTI MODELLO DI STRUTTURE SECONDARIE(1990 – 1996)
3. PEPTIDI BIOATTIVI
NEUROKININA A (1994 - 1998)
4. AMMINOACIDI NON NATURALI E PEPTIDI (1983-2003)
5. INTERAZIONE DI AMMINOACIDI E PEPTIDE CON IONI
METALLICI (1986-1996)
6. MISCELLANEA
Il lavoro scientifico svolto si è concretizzato in 194 pubblicazioni (12 review, 142
lavori, 7 brevetti e 33 proceeding). I lavori a stampa sono tutti su riviste
internazionali ad alta diffusione.
Le ricerche sono state portate avanti interagendo proficuamente con numerosi
ricercatori italiani e stranieri, avvalendosi in tal modo di una collaborazione
1
multidisciplinare e sfruttando nel modo migliore le risorse disponibili.
I risultati scientifici ottenuti sono stati presentati in occasione di convegni
nazionali ed internazionali, come testimoniato dalle numerose comunicazioni
inviate. Il prof. Pavone è stato, inoltre, invitato a tenere numerose conferenze e
seminari sull’attività di ricerca svolta sia in Italia sia all’estero.
L’interesse scientifico del prof. Pavone nel corso degli anni ha riguardato
inizialmente lo studio del riconoscimento molecolare di molecole a base peptidica
da parte di recettori e/o partner proteici e dagli anni ‘90 si occupa prevalentemente
dello studio delle relazioni struttura-funzione delle proteine.
Da un punto di vista metodologico, il prof. Pavone ha una lunga esperienza
nella caratterizzazione strutturale di peptidi e proteine mediante diffrazione di
raggi X, risonanza magnetica nucleare (NMR) e dinamica molecolare. I sistemi
studiati da un punto di vista strutturale sono anche stati caratterizzati da un punto
di vista funzionale.
Le ricerche condotte non solo hanno dato un contributo all’identificazione
dei motivi strutturali fondamentali per l’attività biologica di alcune classi di
proteine, ma anche allo sviluppo di nuovi e potenti farmaci (oggetto di brevetti
internazionali),
(antiasmatici),
quali
antagonisti
inibitori
immunosoppressori
(utili
della
nella
del
recettore
trombina
terapia
dei
della
neurochinina
(antitrombotici),
trapianti,
delle
A
agenti
malattie
autoimmunitarie, dei tumori, ecc.), agenti antivirali (anti-HIV). Molto di recente
è stata anche sviluppata una nuova classe di anti-tumorali basati sul recettore
dell’urochinasi.
In questi ultimissimi anni, le ricerche del Prof. Pavone sono rivolte alla
progettazione e sintesi di proteine artificiali che mostrano un’attività comparabile
o superiore alle proteine naturali. In particolare, una classe di tali molecole
rappresenta un nuovo tipo di potenti e specifici biosensori elettrochimici.
Nelle pagine seguenti saranno descritti in maniera più dettagliata le principali
2
e recenti linee di ricerche (dal punto 1 al punto 3) ed i risultati più rilevanti, senza
voler sminuire gli altri lavori, che hanno dato un contributo significativo alla
comprensione delle proprietà strutturali e funzionali dei sistemi studiati.
Per completezza nell’ultima sezione sono riportati gli abstract di tutte le
review, brevetti, pubblicazioni e proceeding.
3
FERRO-PROTEINE NON-EME
Reviews:
1. Comptes Rendus Chimie (2007), 10(8), 703-720.
2. Biopolymers (2005), 80(2 and 3), 264-278.
3. Annual Review of Biochemistry (1999), 68 779-819.
Pubblicazioni:
4. Journal of Biological Inorganic Chemistry (2005), 10(5), 539-549.
5. Proceedings of the National Academy of Sciences of the United States of
America (2003), 100(7), 3772-3777.
America (2000), 97(12), 6298-6305.
Oltre che nelle eme-proteine, il ferro è presente nei sistemi naturali in
proteine contenenti un centro bimetallico, in cui i due atomi di metallo sono
spesso legati tra loro attraverso uno o più atomi di ossigeno. Questi sistemi sono
caratterizzati dall'assenza di un legante macrociclico rigido e, pertanto, in essi la
coordinazione del metallo avviene attraverso le catene laterali di aminoacidi quali
His, Asp e Glu. In queste molecole, quindi, il metallo costituisce un elemento
strutturale determinante nell'indurre o nello stabilizzare il folding della proteina.
Questi sistemi, unitamente all'uso di modelli di più piccole dimensioni, offrono
buone possibilità per esaminare il processo di inserzione dei metalli nelle proteine
naturali ed il ruolo che tali metalli hanno nel determinare il folding e la stabilità
della
proteina
stessa.
Emeritrina,
Ribonucleotide
reduttasi
e
Metano-
monossigenasi sono esempi di questa classe di proteine. L'Emeritrina è un
trasportatore reversibile di ossigeno, mentre le ultime due catalizzano
rispettivamente la riduzione di ribonucleotidi e l'ossidazione del metano. Le
4
Ferritine costituiscono un altro esempio attraente di “metal-binding proteins”
contenenti ferro; esse contengono un centro binucleare ed uno polinucleare. Le
Bacterioferritine contengono anche un ferro-eme. Il motivo strutturale ricorrente
in tutte le proteine citate è il cosiddetto four-helix bundle, caratterizzato da α-eliche
che aggregano in maniera parallela o antiparallela in strutture tetrameriche.
L'impacchettamento di tali aggregati porta alla costituzione di cavità in cui si
sistema il metallo. I sistemi four helix-bundle rappresentano, quindi, un motivo
strutturale utile ed interessante sia per lo studio dei fattori responsabili del folding
delle proteine, sia perchè sono essenziali building block per la costruzione di molte
proteine biologicamente attive.
Nella Bacterioferritina da Escherichia Coli, nota anche come citocromo b1, di cui è
stata determinata la struttura tridimensionale mediante diffrazione di raggi X, il
sito di binding binucleare è localizzato tra quattro eliche allineate in maniera
antiparallela. Ciascuno dei due atomi di ferro, costituenti il sito bimetallico, è
coordinato attraverso un residuo di His e tre residui di Glu. Due residui di Glu
coordinano entrambi gli ioni metallici formando due ponti tra di essi.
Al fine di ottenere un semplice sistema modello di proteine contenenti il motivo
strutturale four-helix bundle e sfruttando le conoscenze relative alle proprietà
conformazionali degli amminoacidi ed alla loro propensione a dare strutture
5
elicoidali, sono state progettate, usando la metodologia del de novo design, sequenze
peptidiche capaci di dare strutture tetrameriche. In particolare, è stato progettato
un sistema del tipo α2 che dimerizzando porta alla formazione dell’aggregato
tetramerico. Il sistema α2 è costituito da un helix-loop-helix, cioè da da due eliche
antiparallele legate da un loop. Nel design di un appropriato sistema α2 è stato
necessario stabilizzare una corretta conformazione del linker per ottimizzare
specifiche interazioni favorevoli tra le due eliche. L’aggregazione di eliche singole
e di sistemi α2 può avvenire dando luogo ad orientazione parallela od antiparallela
delle unità monomeriche costituenti. Quindi, affinchè l'assemblaggio avvenisse
nella orientazione desiderata, particolare attenzione nel design è stata rivolta alla
costruzione di sequenze capaci di dar luogo ad un buon packing idrofobico e ad
interazioni elettrostatiche che favorissero una orientazione rispetto all'altra.
Infine, è stato costruito in questo scaffold elicoidale il sito di binding dinucleare,
costituito da due residui di His e quattro residui di Glu.
Il primo modello ottenuto è rappresentato schematicamente nelle figure
seguenti, in cui si evidenzia il sito di binding, le interazioni elettrostatiche e il
packing idrofobico.
Il sistema così progettato, denominato DF1 (Due Ferri 1) è stato sintetizzato
mediante sintesi peptidica in fase solida, utilizzando le metodologie classiche della
chimica Fmoc (fluorenilmetossicarbolnile).
È stato, quindi, intrapreso un studio sistematico della capacità di DF1 a legare
differenti ioni metallici, attraverso misure di dicroismo circolare e di spettroscopia
uv-vis.
6
I risultati ottenuti con il Co2+ sono molto incoraggianti, in quanto, come si può
vedere dalla tabella seguente, le proprietà spettroscopiche del modello nella
regione del visibile sono molto simili a quelle della proteina naturale ricostituita
con il cobalto.
λmax
ε
λmax
ε
λmax
ε
(nm)
(M-1cm-1)
(nm)
(M-1cm-1)
(nm)
(M-1cm-1)
Modello
525
120
565
150
605
130
Bacterioferritina
520
126
555
155
600
107
Proteina
Inoltre, studi di folding condotti sia in presenza che in assenza del metallo hanno
dimostrato che la coordinazione influenza positivamente la stabilità del sistema,
per tutta la classe di composti esaminati.
Il sistema modello è anche in
grado di legare ioni ferro o zinco.
La proteina nella forma apo è
stata
completamente
caratterizzata
in
soluzione
mediante NMR. Inoltre, sono
stati
ottenuti
cristalli
del
complesso con lo zinco, adatti ad
uno studio diffrattometrico. È
stata effettuata una raccolta dati
al Centro Elettra, in Trieste, usando luce di sincrotone (risoluzione 2.5 Å, gruppo
spaziale C2221, a = 35.97 Å, b = 89.01 Å, c = 79.66 Å). I risultati ottenuti hanno
confermato pienamente il modello, sia per quanto riguarda la struttura
complessiva della molecola, sia in particolare il sito di coordinazione.
7
Sovrapposizione (in stereo) della struttura cristallina del complesso di-Zn-DF1
(azzurro) con il modello (violetto).
Studi successivi di mutazioni effettuate nella seconda sfera di coordinazione
hanno dimostrato che essa svolge un ruolo chiave nel modulare l’accesso del
metallo al sito attivo. Infatti, Ala13-DF1, che contiene in prossimità del centro
metallico un residuo di alanina al posto della più ingombrante leucina, lega il ferro
più facilmente, anche in condizioni non denaturanti. Inoltre, Ala13-DF1 è stata
cristallizata come complesso di di-Mn(II). Sono stati raccolti i dati di diffrazione
mediante luce di sincrotrone, ad una risoluzione di 1.7 Å. La densità elettronica è
ben definita in prossimità del centro bimetallico, ed è possibile osservare la
presenza di un legante esogeno. Una cavità di dimensioni maggiori è stata
osservata nel composto di-Mn(II)-Gly13-DF1, in cui il residuo di leucina in
posizione 13 è stato sostituito dall’amminoacido meno ingombrato stericamente.
8
EMOPROTEINE
Reviews:
1. Chemical Reviews (Washington, D. C.) (2001), 101(10), 3165-3189
2. Biopolymers (1998), 47(1), 5-22.
Pubblicazioni:
2. Chemistry -A European Journal (2003), 9(22), 5643-5654.
4. Inorganica Chimica Acta (1998), 275-276(1,2), 301-313.
5. Chemistry--A European Journal (1997), 3(3), 350-362.
6. Chemistry--A European Journal (1997), 3(3), 340-349.
L'attività di ricerca svolta dal prof. Pavone nel campo delle eme-proteine è stata
rivolta alla realizzazione di sistemi modello, in cui catene peptidiche di differente
struttura e composizione potessero costituire per l’eme un intorno chimico simile
a quello presente nei sistemi naturali, e riprodurne le loro caratteristiche
essenziali, quali regio- e/o stereo-selettività. Lo studio è stato rivolto ad una
migliore comprensione di come la matrice proteica possa modulare le proprietà e la
reattività del centro metallico. Composizione e struttura della catena proteica in
prossimità dell’eme, sostituenti presenti sull’anello porfirinico, natura dei leganti
assiali e geometria di coordinazione rappresentano tutti fattori importanti nel
determinare le differenti funzioni dell’eme, il cui ruolo può essere meglio
razionalizzato attraverso lo studio di piccole molecole.
È stata, pertanto, sviluppata una nuova classe di sistemi modello di emeproteine, denominati Mimochrome, il cui motivo strutturale caratteristico è un
“sandwich” del tipo elica-eme-elica. Infatti, tali mini-proteine sono costituite da
due segmenti peptidici α-elicoidali legati covalentemente ai gruppi propionici della
deuteroporfirina IX attraverso l'ε-ammino gruppo di un residuo di Lys. In una
9
o in entrambe le catene peptidiche è presente un residuo di His quale legante
assiale del metallo inserito nel nucleo porfirinico. Le strutture schematiche delle
molecole Mimochrome I, Mimochrome II, Mimochrome III e Mimochrome IV
sono riportate di seguito.
R
Mimochrome
N
N
Fe
N
N
O
O
R1
R, R1
I
R=R1 Ac-L-A-Q-L-H-A-N-K-L-NH2
II
R=R1 Ac-D-L-S-D-L-H-S-K-K-L-K-I-T-L-NH2
IV
R=R1 Ac-E-S-Q-L-H-S-N-K-R-NH2
III, V, VI R=
R1=
Ac-D-E-H-K-L-H-S-K-K-R-K-I-T-L-NH2
Ac-D-E-H-K-L-Y-S-K-K-R-K-I-T-L-NH2
Rappresentazione schematica delle molecole Mimochrome
È ben noto che in molte eme-proteine l'α-elica è una delle strutture secondarie
ricorrenti in prossimità del sito attivo. Uno studio approfondito e dettagliato delle
strutture proteiche in prossimità dell'eme nei sistemi naturali ha consentito:
1.
di individuare la minima sequenza aminoacidica in grado di stabilizzare una
conformazione elicoidale della catena peptidica intorno all’eme;
2.
di posizionare correttamente il legante assiale e di renderlo disponibile alla
coordinazione del metallo;
3.
di costituire un intorno sufficientemente idrofobico per l'eme.
Il prototipo della classe, Mimochrome I [3,7,12,17-tetrametilporfirina-2-18-di-
N8ε-(Ac-Leu1-Ala2-Gln3-Leu4-His5-Ala6-Asn7-Lys8-Leu9-NH2)-propionammide] è
10
stato progettato usando l’elica F della catena β della deossiemoglibina come
struttura di riferimento.
Studi di modeling molecolare hanno mostrato che cambiando la conformazione
del gruppo propionico dell’eme e della catena laterale della Lys95 da trans a gauche,
il gruppo carbossilico del propionile e l’ε-ammino gruppo della lisina si sarebbero
portati a distanza di legame. Tale legame covalente ci ha consentito di posizionare
lo scaffold elicoidale in prossimità del centro metallico, in modo che il segmento
peptidico fosse in grado di coprire l’eme in seguito alla coordinazione assiale
dell’istidina.
Opportune sostituzioni apportate nella sequenza originaria, ed una operazione
di simmetria C2 ha condotto alla costruzione del sandwich elica-eme elica.
L’analisi degli spettri UV-visibili delle molecole come base libera e nella forma
coordinata a ioni metallici nelle regioni caratteristiche del nucleo porfirinico
(regione di Soret e regione β/α) ha evidenziato l’inserzione di ioni metallici
(Fe(II), Fe(III), Co(III)) nell'anello porfirinico ed una coordinazione del tipo bis-
11
istidina, come previsto dal modello.
Le proprietà conformazionali della parte peptidica sono stata analizzate
mediante tecniche di dicroismo circolare (CD). Secondo le nostre aspettative, le
catene peptidiche assumono una conformazione elicoidale, sia nella base libera che
nei sistemi contenenti il metallo, come dimostrato dai loro spettri CD tipici di αeliche.
A differenza del complesso con il ferro, il complesso Co(III)-Mimochrome I si
è presentato sotto forma di due isomeri stabili, separabili in HPLC; essi hanno
però evidenziavano effetti Cotton nella regione di Soret di diversa intensità e di
segno opposto. I due isomeri sono stati definitivamente identificati via NMR,
come diastereoisomeri di tipo ∆ e Λ del complesso ottaedrico.
Le catene peptidiche dell’isomero
∆ adottano una conformazione αelicoidale piuttosto regolare, con una
parziale distorsione verso l’elica 310
nella parte C-terminale. Le due
eliche sono circa antiparallele e
correlate da uno pseudo asse di
simmetria C2.
Nell’isomero
Λ,
invece,
la
conformazione delle due catene
peptidiche risulta meno
regolare.
L’insieme dei risultati ottenuti su Mimochrome I e del suo derivato contenente
cobalto hanno costituito una base rilevante per la progettazione e la sintesi di una
seconda generazione di molecole. Si è cercato di migliorare il modello iniziale
favorendo una singola topologia strutturale e cercando così di evitare la
formazione dei due possibili isomeri.
12
Mimochrome II e Mimochrome III, sono costituiti da due catene peptidiche di
14 residui. I primi 10 residui sono stati modellati in conformazione elicoidale,
mentre la parte C-terminale in conformazione estesa. Le due catene peptidiche
sono in grado di avvolgere completamente la porfirina, in modo da renderla
inaccessibile al solvente e da sfavorire fenomeni di aggregazione tra i nuclei
porfirinici.
L’analisi delle proprietà spettroscopiche e dicroiche del composto Co(III)Mimochrome II ha evidenziato l’esistenza di una singola specie. Inoltre, un
confronto
con
l’analogo
complesso
Mimochrome
I
ha
suggerito
che
l’organizzazione strutturale del composto Co(III)-Mimochrome II corrisponda
all’isomero ∆.
Mimochrome III si differenzia dalle due precedenti molecole per la differente
composizione amminoacidica delle due catene peptidiche.
Essa è stata progettata allo scopo di stabilizzare un complesso del ferro
pentacoordinato e, pertanto, un residuo di istidina in una catena è stato sostituito
con un residuo di serina, non adatto a coordinare il metallo. Nella cavità che si
13
crea in prossimità del centro metallico potrebbe essere ospitato un legante esogeno,
quale una molecola di CO, NO, O2, H2O2. Una preliminare caratterizzazione ha
messo in evidenza anche in questa nuova molecola l’esistenza di una singola
specie.
Un differente approccio per la stabilizzazione di una singola specie ha
riguardato l'introduzione alle estremità N- e C-terminali di residui atti a
stabilizzare la struttura a sandwich mediante la formazione di coppie ioniche
intercatena. A tale scopo è stata progettata e sintetizzata una nuova molecola,
Mimochrome IV, le cui catene peptidiche sono costituite da 9 ammino acidi, come
in Mimochrome I, ma che si differenzia da quest’ultima per la presenza di residui
di acido glutammico e di arginina rispettivamente nelle posizioni 1 e 9. Anche in
questo caso la caratterizzazione mediante CD nelle regione di Soret ha evidenziato
la presenza preponderante di una unica specie; questo risultato è stato poi
confermato da una caratterizzazione strutturale in soluzione mediante NMR.
Gli effetti della parte peptidica nella modulazione delle proprietà del centro
metallico sono stati analizzati mediante studi di reattività nei confronti di diversi
leganti (quali, CO, NO ed alchi-idrossil-ammine) e di catalisi di particolari
reazioni. Gli studi di attività catalitica hanno dimostrato la capacità del complesso
Fe(III)-Mimochrome I di catalizzare reazioni di idrossilazione in mezzo acquoso
in presenza di un agente ossidante pulito, quale l’acqua ossigenata; inoltre, la
catena peptidica svolge un ruolo fondamentale nel proteggere l'anello porfirinico
da reazioni di degradazione. Sebbene questi dati siano solo preliminari, ciò
rappresenta un risultato di notevole rilevanza e prova che è possibile costruire
catalizzatori basati su semplici porfirine naturali, modulandone le proprietà, quali
solubilità e resistenza alla degradazione, progettando in modo opportuno uno
specifico intorno peptidico.
14
PROTEINE FERRO-ZOLFO
Miniaturized Electron Transfer Proteins (METP)
Brevetti:
1. Pseudo-metalloproteins, their preparation and use in biosensors.
WO2002012278 A2 20020214
Pubblicazioni:
America (2000), 97(22), 11922-11927.
L’interesse scientifico del prof. Pavone è stato rivolto verso le proteine ferrozolfo. I centri Fe/S in alcuni casi sono presenti come sistemi isolati all'interno
delle proteine; più spesso, però, mostrano forti interazioni con altri gruppi
prostetici o altri centri metallici (Ni, Mo, V, Fe-eme, flavine). La loro principale
caratteristica strutturale è rappresentata dalla coordinazione dello ione ferro da
parte dello zolfo delle cisteine della catena proteica (RS-), e, nei centri polinucleari,
da solfuro inorganico acido-labile (S2-). I centri Fe/S possono essere classificati, in
accordo con il loro grado di aggregazione nel cluster, in [1Fe-0S], [2Fe-2S], [3Fe4S] e [4Fe-4S] in base al numero di atomi di ferro e di zolfo non proteico presenti.
Le rubredossine sono le più semplici proteine ferro-zolfo, esse sono piccole proteine
presenti in alcuni batteri anaerobici, dotate di un potenziale di riduzione compreso
tra -57 e 6 mV. Il centro redox attivo nelle rubredossine, [1Fe-0S], consiste in uno
ione ferro ad alto spin, coordinato da quattro residui di cisteine in una geometria
tetraedrica distorta. Dall’analisi delle strutture di alcune rubredossine le sequenze
amminoacidiche mostrano un pattern dei residui coordinanti il metallo che è
costituito da due set di coppie di Cys, ciascuna separata da due amminoacidi in
una sequenza del tipo -Cys-x-y-Cys-Gly-z.
Il lavoro del prof. Pavone nello studio delle proteine ferro-zolfo ha avuto inizio
con un’analisi attenta della struttura della rubredossina da Desulfovibrio Vulgaris,
15
osservando
che,
enucleando
dall’intera proteina i residui compresi
in una sfera di 9 Å intorno al centro
metallico,
organizzata
la
in
catena
modo
peptidica
è
simmetrico
rispetto al centro metallico. Un asse
di simmetria C2 del tetraedro di
coordinazione relaziona due segmenti
peptidici di circa 10 amminoacidi
ciascuno.
Struttura ai raggi X della rubredossina
da Desulfovibrio Vulgaris.
(a)
(b)
(a) Segmenti della sequenza amminoacidica della rubredossina da Desulfovibrio Vulgaris
contenenti i residui di Cys coordinanti in cui è evidenziata la simmetria del sito metallico;
(b) modelli molecolari derivanti dalla rotazione binaria di ciascun segmento di catena, di
dieci amminoacidi, contenenti i residui coordinanti.
L’applicazione delle metodologie di design, seguendo un approccio
minimalistico, ha consentito la progettazione di una prima molecola, denominata
METP (Miniaturized Electron Transfer Protein). Tale molecola è costituita da un
omodimero formato da due sequenze peptidiche costituite da 11 residui
16
aminoacidici; la dimerizzazione ha luogo a seguito della coordinazione dei residui
di cisteina a ioni metallici, riproducendo le proprietà della rubredossina naturale.
METP
Ac- Cys-Thr-Lys-Cys-Gly-Ala-Asn-Aib-Ser-Glu-Ile-NH2
Rd[5-16]
Val-Cys-Thr-Val-Cys-Gly-Tyr-Glu-Tyr-Asp-Pro-Ala-
Rd[38-49]
Val-Cys-Pro-Val-Cys-Gly-Ala-Pro-Lys-Ser- Glu-Phe-
Il complesso omodimerico è stabilizzato da interazioni inter-catena di tipo
idrofobico tra i residui di Ile C-terminali e di tipo ionico tra il residuo di Lys di
una catena e quello di Glu dell’altra. La molecola dimerizza in presenza di ferro,
cobalto e zinco, mostrando proprietà spettroscopiche del tutto analoghe a quelle
della rubredossina naturale, e tipiche di un complesso con geometria di
coordinazione tertraedrica.
Spettri UV/Vis Co(II)-METP (sinistra) e Fe(II)/Fe(III)-METP (destra).
La corretta stechiometria del complesso Co(II)-METP e la maggiore affinità di
METP per lo Zn(II), rispetto al Co(II), confermano il modello e sono in pieno
accordo con una coordinazione tetraedrica.
Il complesso Zn(II)-METP è stato anche caratterizzato strutturalmente in
soluzione mediante NMR. Lo spettro monodimensionale, riportato di seguito, ha
mostrato un’ottima dispersione di segnali, indice di strutturazione della molecola.
Inoltre, lo spettro mostra un unico set di segnali, in accordo con la simmetria C2
della molecola. L’analisi degli spettri bidimensionali ha confermato che la
molecola adotta in soluzione una struttura molto simile a quella della proteina
naturale ed al modello proposto.
17
Regione amminica dello spettro protonico del complesso Zn(II)-METP in CD3OH a
298 K
Gli incoraggianti risultati ottenuti con il primo modello hanno indotto a
proseguire le ricerche, cercando di costruire una collezione di modelli analoghi,
ML1L2L3L4, con differenti residui coordinanti (L= Cys, Dap, His, Glu, Asp, ecc), e
contenenti ioni metallici con diverse proprietà elettroniche, redox e di
coordinazione (M= Co, Fe, Mn, Zn, Cd, Ni, ecc.). A tale scopo è risultata
necessaria la progettazione di sistemi eterodimeri in cui il complesso metallico si
formi in seguito alla dimerizzazione di
due catene peptidiche diverse.
Sono state già progettate e sintetizzate
sequenze
peptidiche
opportunamente
modificate rispetto al prototipo METP
sia nella prima che nella secoda sfera di
coordinazione.
Modelli molecolari dei complessi
METP omo- ed etero-dimeri.
18
IL RECETTORE DELL’UROCHINASI (UPAR)
Pubblicazioni:
1. FEBS Letters (2008), 582(7), 1141-1146.
Brevetti:
2. WO 2008017372 A1 20080214
Il recettore dell’urochinasi (uPAR) gioca un ruolo chiave nei processi fisiologici e
patologici sostenuti da una alterata migrazione cellulare. Esso è formato da tre
domini ed è ancorato alla membrana cellulare mediante un gruppo GPI. uPAR
forma complessi con diverse proteine transmembrana e questa interazione
consente la trasmissione del segnale. Pertanto, uPAR può svolgere molteplici
funzioni a seconda della proteina transmembrana con cui interagisce. uPAR è
attivato dall’urochinasi (uPA) che causa una idrolisi dell’uPAR liberando il
domino N-terminale. L’interazione uPAR-uPA causa l’esposizione del segmento
peptidico
Ser88-Arg-Ser-Arg-Tyr92
(SRSRY)
che
possiede
proprietà
chemotattiche. E’ stato individuato un peptide di 5 amminoacidi che antagonizza
l’interazione di uPAR o del peptide SRSRY con il recettore transmembrana FPR.
Questo antagonismo si riflette in una ridotta motilità cellulare direzionata. E’
stata successivamente identificata una nuova classe di peptidi che può trovare
applicazione in numerose patologie come i processi infiammatori cronici e nei
tumori.
19
RANTES
Pubblicazioni:
1. Biochemical and Biophysical Research Communications (2006), 351(3), 664668.
2. Nature Structural Biology (2001), 8(7), 611-615.
Brevetti:
3. WO 2004065406 A2 20040805
4. WO 2000027880 A2 20000518
Le terapie attualmente in uso per l’infezione da HIV mostrano severe limitazioni.
In particolare esse richiedono l’uso concertato di una miscela di farmaci che
agiscono a vari stadi della replicazione del virus, ma non sono capaci di bloccare
l’ingresso del virus in nuove cellule linfocitarie. Ai farmaci attualmente in uso
sono associate tossicità piuttosto elevate che in alcuni casi ne limtano l’uso.
Numerosi sforzi sono stati fatti per lo sviluppo di vaccini, ma attualmente non
esistono preparati soddisfacenti. È, infatti, da considerare che i pazienti affetti da
infezione da HIV sono immunodepressi e, quindi, la reazione di stimolazione
immunitaria da vaccino può essere piuttosto ridotta. Da questo quadro di
riferimento è emersa la necessità di sviluppare metodi alternativi per sconfiggere
l’AIDS.
La strategia intrapresa dal prof. Pavone è stata quella di realizzare un sistema che
impedisce all’HIV di entrare nelle cellule linfocitarie. Il virus adopera due
recettori per entrare nella cellula linfocitaria: CCR5 e CD4. Per impedire l’ingresso
del virus nella cellule linfocitarie basterebbe occupare il recettore CCR5 che,
quando pieno, non potrebbe assistere il virus per penetrare nelle cellule.
La chemochina specifica per il recettore CCR5 è RANTES, una piccola proteina
che stimola il sistema immunitario. Studiando RANTES è stato possibile
individuare
due
regioni
idrofobiche
della
sua
superficie
responsabili
20
dell’interazione specifica con CCR5.
Sulla base dell’orientazione relativa
nello spazio di questi due domini
idrofobici, come ricavato dalla struttura
tridimensionale di RANTES, è stato
possibile
composti
sviluppare
che
una
serie
beneficamente
di
non
stimolano il sistema immunitario e
parallelamente inibiscono la fusione del
virus con la cellula linfocitaria.
Queste nuove molecole possono trovare
numerose
terapeutiche.
altre
Ad
applicazioni
esempio,
possono
essere adoperate come antivirali. La classe dei mimetici del CD4 possono in
aggiunta trovare applicazione nelle malattie autoimmuni, come l’artrite
reumatoide, la sclerosi multipla e nel trattamento post-operatorio di trapianto
d’organo.
21
TROMBINA
Review:
1. Biopolymers (1999), 51(1), 19-39.
2. Biological Chemistry (1998), 379(8/9), 987-1006.
Pubblicazioni:
3. Protein Science (1999), 8(1), 91-95.
4. Protein Science (1998), 7(2), 243-253.
Risultati di rilievo sono stati anche ottenuti nello sviluppo di una nuova classe
di potenti inibitori sintetici della trombina, denominati Hirunorms, potenziali
candidati in applicazioni terapeutiche.
Vista stereo della sovrapposizione degli atomi del backbone tra l’irudina
(da Ile1’ ad Asp5’ e da Glu49’ a Gln65’, in blu) ed hirunorm IV
(da Chg1” ad Asp5” e da Glu10” a D-Glu26”, in rosso)
Il più potente inibitore naturale della trombina è l’irudina, una piccola proteina
22
di 65 amminoacidi, che lega specificamente la trombina con un valore di Ki di 2.2 .
10-14 M, inibendo il taglio del fibrinogeno e la formazione di coaguli di fibrina.
Sulla base della recente risoluzione delle strutture cristalline del complesso
irudina-trombina e di complessi della trombina con inibitori sintetici, abbiamo
“razionalmente” progettato e sintetizzato una serie di composti peptidici, di basso
peso molecolare, capaci di agire, in maniera simile all’irudina, da inibitori “multisito” della trombina.
Le strutture cristalline dei complessi della trombina con gli inibitori
hirunorm IV ed hirunorm V sono state recentemente risolte. Esse hanno
pienamente confermato il nostro modello iniziale ed il modo di binding previsto,
simile a quello dell’irudina. Infatti, le molecole Hirunorms, in maniera analoga
all’irudina, interagiscono con la trombina con il tetrapeptide N-terminale,
allineando il backbone in maniera parallela a quello dell’enzima. Allo stesso tempo
l’inibitore si lega in maniera specifica con la parte C-terminale al sito di
riconoscimento del fibrinogeno.
I risultati ottenuti hanno dimostrato ancora una volta la stretta correlazione
esistente tra struttura e funzioni e la possibilità di poter ottenere molecole
sintetiche dotate di proprietà analoghe rispetto ai composti naturali.
Struttura del complesso Hirunorm IV – α-trombina,
come ottenuta da analisi diffrattometrica
23
STRUTTURA SECONDARIA DELLE PROTEINE
Review:
1. Biopolymers (1993), 33(7), 1037-49.
Pubblicazioni:
2. Biopolymers (1996), 38(6), 705-721.
3. Biopolymers (1996), 38(6), 693-703.
4. Biopolymers (1996), 38(6), 683-691.
5. Biopolymers (1994), 34(11), 1517-26.
6. Biopolymers (1994), 34(11), 1505-15.
7. Biopolymers (1993), 33(4), 621-31.
9. Biopolymers (1992), 32(2), 173-83.
10. Gazzetta Chimica Italiana (1991), 121(1), 21-7.
11. Biopolymers (1991), 31(1), 129-38.
12. Biopolymers (1991), 31(10), 1181-8.
13. Journal of the Chemical Society, Perkin Transactions 2: Physical
Organic Chemistry (1972-1999) (1990), (11), 1829-37.
14. Journal of Biomolecular Structure & Dynamics (1990), 7(6), 1321-31.
15. International Journal of Biological Macromolecules (1988), 10(4), 238-40.
16. Journal of Molecular Biology (1990), 214(3), 633-5.
17. Biopolymers (1990), 30(1-2), 189-96.
18. Journal of Biomolecular Structure & Dynamics (1988), 5(4), 803-17.
19. Biopolymers (1989), 28(1), 215-23.
20. Biopolymers (1989), 28(1), 203-14.
21. Biopolymers (1989), 28(1), 193-201.
22. Proceedings of the National Academy of Sciences of the United States
of America (1986), 83(7), 1988-92.
24
L’esame di un gran numero di strutture tridimensionali di proteine è stata
utilizzato dal prof. Pavone per uno studio dettagliato sulla conformazione di “αturn” isolati. Strutture secondarie irregolari, quali appunto “α-turn” isolati (che
non fanno cioè parte di α-eliche), sono importanti domini strutturali coinvolti in
processi di riconoscimento molecolare e nel “folding” di proteine. L’analisi
condotta sulle strutture di proteine riportate nel “Protein Data Bank” ha
consentito una razionale classificazione di tale motivo strutturale in 9 classi
distinte, sulla base del segno degli angoli diedri φi+1, φi+2, e φi+3. È stato, inoltre,
condotto uno studio preliminare per analizzare la frequenza dei vari amminoacidi
in particolari posizioni del “turn”.
Nomenclatura proposta per gli α-turn sulla base del segno degli angoli
φi+1, φi+2, φi+3 .
I-αRS
φi+1
-
φi+2
-
φi+3
-
I-αLS
+
+
+
II-αRS
-
+
-
II-αLS
+
-
+
I-αLU
-
+
+
I-αRU
+
-
-
II-αLU
-
-
+
II-αRU
+
+
-
names
Il prof. Pavone ha anche proposto una nuova nomenclatura e classificazione per i
β-hairpin. In particolare, è stato proposto un nuovo criterio per distingure i residui
amminoacidici appartenenti al loop da quelli caratteristici del tratto βantiparallelo, basato sui possibili schemi di legame idrogeno osservati nelle
strutture proteiche. Questa analisi ha permesso di classificare i β-hairpin in 4
differenti classi ed è stato possibile proporre una semplice relazione esistente tra i
25
membri di una stessa classe.
Inoltre, durante i suoi studi, il prof. Pavone ha individuato strutture molto
particolari e, all’epoca, poco conosciute, come ad esempio il β-bend ribbon spiral,
l’elica 310, doppie eliche o strutture tubulari tipo nanotubi.
Struttura del β-bend ribbon spiral
Elica 310
Una ulteriore strategia adoperata per individuare le particolarità di strutture
secondarie è consistito nello studio di peptidi ciclici. Tuttavia, anche se il vincolo
topologoco
della
ciclizzazione
riduce
considerevolmente
la
flessibilità
conformazionale in confronto al precursore lineare, i peptidi ciclici sono ancora
26
molecole flessibili.
β-Amminoacidi incorporati in peptidi ciclici possono fornire domini
strutturali ben definiti e rappresentano importanti “attrezzi molecolari” per la
stabilizzazione di particolari conformazioni. E’ stata intrapresa una analisi
sistematica sulle preferenze conformazionali di peptidi ciclici contenenti βalanine.
Abbiamo ipotizzato e successivamente verificato sperimentalmente che:
•
Il segmento dipeptidico β-alanil-β-alanina può assumere le posizioni 1 ed n+1
di (a) un “γ-turn” in un tripeptide ciclico (n=2); (b) un “β-turn” in un
tetrapeptide ciclico (n=3); (c) un “α-turn” in un pentapeptide ciclico (n=4).
•
Il segmento tripeptidico β-Ala-Pro-β-Ala può stabilizzare un “γ-turn” intorno
al residuo di prolina e, quando incorporato in un tetrapeptide ciclico, può
forzare il quarto amminoacido ad adottare una conformazione “γ-turn”.
β
L’analisi strutturale condotta allo
stato solido sul peptide ciclo-(L-ProL-Phe-β-Ala-β-Ala) ha dimostrato
che il dipeptide -β-Ala-β-Ala può
essere convenientemente utilizzato
per forzare il resto della molecola in
una conformazione di tipo “β-turn”.
Infatti il composto mostra un
legame idrogeno intramolecolare tra
il gruppo CO di βAla4 e l’NH di β-Ala3, stabilizzando un “β-turn” di tipo I, in cui
i residui di prolina e fenilalanina occupano rispettivamente le posizioni 2 e 3.
27
I tetrapeptidi ciclici c-(L-Pro-β-Ala-L-Pro-βAla) e c-(L-Pro-β-Ala-L-Val-β-Ala) sono
stati caratterizzati sia in soluzione che allo
stato solido. I dati NMR ottenuti in soluzione
di acetonitrile hanno pienamente confermato
le nostre ipotesi, mostrando che la
conformazione, in entrambe le molecole, è
caratterizzata da due “γi-turn”, in cui gli αamminoacidi occupano la posizione centrale.
Allo stato solido, mentre il primo composto
conserva la conformazione trovata in
soluzione, il secondo presenta una inaspettata
conformazione, stabilizzata da legami
idrogeno intermolecolari; nessun legame
idrogeno intramolecolare è, invece, presente.
In conclusione, gli studi condotti sui peptidi ciclici contenenti β-alanine hanno
dimostrato che questi residui sono capaci di indurre peculiari conformazioni,
suggerendo che β-amminoacidi possono essere utilizzati come convenienti “tool”
molecolari e possono essere incorporati in molecole di dimensioni maggiori, per
stabilizzare ben definiti elementi strutturali.
28
NEUROKININA A
Review:
1. Regulatory Peptides (1996), 65(1), 55-59.
Brevetti:
2. WO 9731941 A2 19970904
3. WO 9321227 A1 19931028
Pubblicazioni:
4. Bioorganic & Medicinal Chemistry Letters (1998), 8(13), 1735-1740.
5. Bioorganic & Medicinal Chemistry Letters (1998), 8(10), 1153-1156.
7. Journal of Peptide Science (1995), 1(4), 236-40.
8. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic
Chemistry (1995), (5), 987-93.
9. Journal of Pharmacology and Experimental Therapeutics (1994), 271(3),
1489-500.
I risultati ottenuti nei primi anni dell’attività di ricerca sulle preferenze
conformazionali di peptidi ciclici contenenti β-amminoacidi sono stati
opportunamente adoperati nella progettazione di un peptide biciclico, denominato
Men 10627 [ciclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)ciclo(2β-5β)], potente e selettivo
antagonista della Neurochinina A. La realizzazione di tale composto è stato anche
oggetto di brevetti internazionali.
La Neurochinina A (NKA) appartiene alla famiglia delle tachichinine,
peptidi largamente distribuiti nel sistema nervoso centrale e periferico. Essi
rivestono una varietà di ruoli importanti e ciò ha stimolato un grande interesse
29
verso la possibilità di modulare o di bloccare la loro azione attraverso lo sviluppo
di specifici antagonisti.
Le tachichinine riconoscono, anche se con diversa affinità, tre differenti
recettori: NK1, NK2 ed NK3; questa osservazione ci ha portato ad ipotizzare che
queste molecole possono assumere in soluzione almeno tre differenti
conformazioni, ciascuna delle quali si accomoda in un differente sito recettoriale.
Tale ipotesi è supportata da una analisi strutturale condotta su diversi agonisti ed
antagonisti, che ha mostrato che queste molecole sono estremamente flessibili in
soluzione e distribuite in un gran numero di famiglie conformazionali. Si è,
pertanto, cercato di “costruire” un antagonista della NKA, costretto in una ben
determinata conformazione, che interagisse con maggiore affinità e selettività con
il suo recettore primario NK2.
Sulla base dei dati disponibili in letteratura, si è ipotizzato che una struttura
contenente due “β-turn” fosse responsabile dell’interazione della NKA con il
recettore NK2 ed abbiamo, quindi, cercato di riprodurre tale struttura in una
“impalcatura” rigida. Utilizzando le nostre conoscenze sulle preferenze
confomazionali di tetrapeptidi ciclici contenenti due β-alanine consecutive,
abbiamo sviluppato un modello corrispondente a due tetrapeptidi ciclici “fusi”
insieme, ciascuno contenente un “β-turn”.
Men 10627 assume la conformazione prevista nella fase di progettazione e si è
rivelato il più potente e selettivo
antagonista della NKA, dimostrando
che
è
una
tridimensionale
rigida
struttura
è
requisito
il
essenziale per lo sviluppo di molecole
dotate di specifiche funzioni.
Successivamente, è stato sviluppato un nuovo analogo denominato
30
Neuronorm. Esso è un composto di grande interesse applicativo, in quanto, oltre a
possedere elevata potenza e selettività, presenta anche una buona solubilità in
acqua. Quest’ultima importante caratteristica è conferita dalla presenza di
un’unita glicosilica. Lo sviluppo di questo composto è stato oggetto di un brevetto
internazionale.
31
REVIEWS
1. Diiron-containing metalloproteins: Developing functional models. Maglio,
Ornella, Nastri, Flavia, Martin de Rosales, Rafael Torres, Faiella, Marina,
Pavone, Vincenzo, DeGrado, William F., Lombardi, Angela. Comptes
Rendus Chimie (2007), 10(8), 703-720.
Abstract: A review. A major objective in protein science is the design of
enzymes with novel catalytic activities that are tailored to specific
applications. Such enzymes may have great potential in biocatalysis and
biosensor technol., such as in degrdn. of pollutants and biomass, and in drug
and food processing. To reach this objective, investigations into the basic
biochem. functioning of metalloproteins are still required. In this
perspective, metalloprotein design provides a powerful approach first to
contribute to a more comprehensive understanding of the way
metalloproteins function in biol., with the ultimate goal of developing novel
biocatalysts and sensing devices. Metalloprotein mimetics have been
developed through the introduction of novel metal-binding sites into
naturally occurring proteins as well as through de novo protein design. We
have approached the challenge of reproducing metalloprotein active sites by
using a miniaturization process. We centered our attention on iron-contg.
proteins, and we developed models for heme proteins and diiron-oxo
proteins. In this paper we summarize the results we obtained on the design,
structural, and functional properties of DFs, a family of artificial diiron
proteins.
2. Artificial diiron proteins: From structure to function. Calhoun, Jennifer R.,
Nastri, Flavia, Maglio, Ornella, Pavone, Vincenzo, Lombardi, Angela,
DeGrado, William F. Biopolymers (2005), 80(2 and 3), 264-278.
Abstract: A review. De novo protein design provides an attractive approach
for the construction of models to probe the features required for the
function of complex metalloproteins. These minimal models contain the
essential elements believed necessary for activity of the protein. Here, the
authors summarize the design, structure detn., and functional properties of
a family of artificial diiron proteins which include DF1, DF2, DF2t, and
DFsc.
3. Peptide-Based Heme-Protein Models. Lombardi, Angela, Nastri, Flavia,
Pavone, Vincenzo. Chemical Reviews (Washington, D. C.) (2001), 101(10),
3165-3189.
Abstract: A review, with refs. Topics discussed include: developing heme-
32
protein mimetics; spectral properties of metalloporphyrins and hemeproteins; covalent peptide-porphyrin systems; and noncovalent peptideporphyrin systems.
4. From natural to synthetic multisite thrombin inhibitors. Lombardi Angela,
De Simone Giuseppina, Galdiero Stefania, Staiano Norma, Nastri Flavia,
Pavone Vincenzo. Biopolymers (1999), 51(1), 19-39.
Abstract: A large number of potent and selective therapeutic agents, useful
for the treatment of several diseases, have been isolated from natural
sources. For example, the most active thrombin inhibitors are those secreted
by the salivary glands of leeches. One peculiar feature of these agents is the
lack of any significant inhibitory cross-reaction with other serine
proteinases. Hence, the knowledge of the exact mechanism of action of
these molecules provides the basis for the development of new and efficient
synthetic drugs. For this reason, many studies have been undertaken on the
structure-activity relationships of natural thrombin inhibitors, and a large
amount of detailed information has been obtained by the crystal structures
of these inhibitors when complexed with thrombin. In this paper, we
review natural and synthetic multisite thrombin inhibitors, whose
structural aspects have been determined in detail. We also report here the
approach used by us to develop a new class of synthetic, multisite directed
thrombin inhibitors, named hirunorms, designed to mimic the distinctive
binding mode of hirudin.
5. De
novo design and structural characterization of proteins and
metalloproteins. DeGrado, William F., Summa, Christopher M., Pavone,
Vincenzo, Nastri, Flavia, Lombardi, Angela. Annual Review of Biochemistry
(1999), 68 779-819.
Abstract: A review with 309 refs. De novo protein design has recently
emerged as an attractive approach for studying the structure and function of
proteins. This approach critically tests our understanding of the principles
of protein folding; only in de novo design must one truly confront the issue
of how to specify a protein's fold and function. If proteins can be truly
understood, it should be possible to design receptors, enzymes, and ion
channels from scratch. Further, as this understanding evolves and is further
refined, it should be possible to design proteins and biomimetic polymers
with properties unprecedented in nature.
6. Miniaturized hemoproteins. Nastri, Flavia, Lombardi, Angela, D'Andrea,
Luca D., Sanseverino, Marina, Maglio, Ornella, Pavone, Vincenzo.
Biopolymers (1998), 47(1), 5-22.
33
Abstract: A review, with .apprx.114 refs. The present paper highlights and
reviews current research in the field of hemoprotein models. Hemoproteins
have been extensively studied in order to understand structure-function
relationships, and to design new mols. with desired functions. A wide no. of
synthetic analogs have been developed, using quite different approaches.
They differ in mol. structures, ranging from simple meso-substituted
tetraaryl-metalloporphyrins and peptide-porphyrin conjugates. In this paper
we summarize the state of the art on peptide based hemoprotein models.
We also report here the approach used by us to develop a new class of mols.,
named mimochromes. They can be regarded as miniaturized hemoproteins,
because mimochromes are low mol. wt. compds. with some structural and
functional properties common to those of the parent high mol. wt. protein.
The basic structure of mimochromes is a deutero-porphyrin ring covalently
linked to two helical peptide chains. Two mols. of this series have been
fully characterized. All the information derived from their structural anal.
has been applied to the design of new analogs with addnl. functions.
7. Multiple binding mode of reversible synthetic thrombin inhibitors. A
comparative structural analysis. Pavone, Vincenzo, De Simone,
Giuseppina, Nastri, Flavia, Galdiero, Stefania, Staiano, Norma, Lombardi,
Angela, Pedone, Carlo. Biological Chemistry (1998), 379(8/9), 987-1006.
Abstract: A review is given with many refs. on the state of the art on
reversible thrombin inhibitors. The authors discuss some structural aspects
of thrombin-inhibitor interaction, which account for the different affinity
and potency of these mols. The central role of the Ser protease thrombin in
hemostasis and thrombosis brought the development of highly potent and
selective thrombin inhibitors. Thrombin-inhibitor complexes have
extensively been studied to understand structure-function relationships, and
to design new inhibitors that can be used with broader efficacy over existing
antithrombotic agents. The authors also report the approach to develop a
new class of synthetic, multisite-directed thrombin inhibitors, named
hirunorms, designed to mimic the distinctive binding mode of hirudin. The
authors emphasize that, despite the high specificity of thrombin action, the
interaction of inhibitors in its active site may occur with quite different
mechanisms.
8. A review of the design, synthesis and biological activity of the bicyclic
hexapeptide tachykinin NK2 antagonist MEN10627. Quartara, Laura,
Pavone, Vincenzo, Pedone, Carlo, Lombardi, Angelina, Renzetti, Anna
Rita, Maggi, Carlo Alberto. Regulatory Peptides (1996), 65(1), 55-59.
34
Abstract: A review with 29 refs. We review the reported data on the design,
the conformational features and the pharmacol. properties of the bicyclic
peptide tachykinin NK2 receptor antagonist MEN 10,627 or cyclo(Met-Asp
-Trp-Phe-Dap-Leu)cyclo(2β-5β). MEN 10,627 possesses a highly constrained
structure characterized by two consecutive β-turns, as confirmed by the
almost coincident results of NMR and x-ray analyses. The compd. has been
efficiently synthesized by solid-phase methodol. using either Boc or Fmoc
strategies. It is quite stable to metabolic degrdn. and is endowed with high
affinity and selectivity for NK2 receptor expressed in various species. At
the hamster NK2 receptor MEN 10,627 is about 30-fold more potent than the
nonpeptide NK2 receptor antagonist, SR 48,968, while the converse is true
for the rabbit NK2 receptor. MEN 10,627 and SR 48,968 show comparable
affinities for the human NK2 receptor. MEN 10,627 produces a long lasting
inhibition of the response to the selective NK2 receptor agonist
[βAla8]NKA(4-10) in the rat urinary bladder in vivo after i.v., intranasal
and intraduodenal administration. Therefore different administration
routes are possible for this compd. that overcomes the usual drawbacks for
the application of peptides as drugs.
9. Noncoded residues as building blocks in the design of specific secondary
structures: symmetrically disubstituted glycines and β -alanine. Di Blasio,
Benedetto, Pavone, Vincenzo, Lombardi, Angela, Pedone, Carlo, Benedetti,
Ettore. Biopolymers (1993), 33(7), 1037-49.
Abstract: A review with 98 refs. Structural changes can be induced in a
peptide by selective substitution of coded α-amino acid residues by
noncoded α-amino acid residues and the consequent prodn. of analogs with
modified structure and conformational preferences. This review
summarizes the solid state structural results and the conformational
preferences of two classes of "building blocks": (a) the linear and cyclic sym.
α,α-disubstituted glycines in which either two identical n-alkyl groups
replace the hydrogen atoms of the glycine residue or a cyclic aliph. sidechain system is formed by linking the two α-carbon side chains, resp.; and
(b) the β-alanine residue. Examples, whenever possible, of the use of these
residues for the elucidation of the bioactive conformation in the appropriate
biol. systems are given.
10. Structure-activity relationships in bioactive peptides. Benedetti, Ettore, Di
Blasio, Benedetto, Pavone, Vincenzo, Pedone, Carlo. Colloque INSERM
(1989), 174, 27-40.
Abstract: A review and discussion with 66 refs., on bioactive peptide
functions (e.g., mol. recognition, membrane interactions) dependence
35
on conformation and structure, giving as examples (1) antibiotic ionophores,
gramicidin A and alamethicin and (2) toxins or toxin antagonists from
Amanita mushrooms. Methods for correlation of physicochem. data with
structural and conformational parameters are included.
11. Preferred structures of constrained peptides from achiral α,α-dialkylated
glycyl residues with acyclic side chains. Benedetti, Ettore, Di Blasio,
Benedetto, Pavone, Vincenzo, Pedone, Carlo, Bavoso, Alfonso, Toniolo,
Claudio, Bonora, Gian Maria, Leplawy, Miroslaw T, Hardy, Paul M. Journal
of Biosciences (Bangalore, India) (1985), 8(1-2), 253-62.
Abstract: A review with 28 refs. on conformational analyses of the title
peptides by conformational energy computation, IR and H-NMR
spectroscopy, and x-ray diffraction. The relation of conformational
preference to side-chain bulkiness is discussed.
12. Preferred conformations of peptides containing α,α-disubstituted α-amino
acids. Toniolo, Claudio; Bonora, Gian Maria; Bavoso, Alfonso; Benedetti,
Ettore; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo. Biopolymers
(1983), 22(1), 205-15.
Abstract: A review with 63 refs. on the conformations of αaminoisobutyrate- and isovaline-substituted peptides.
36
BREVETTI
1.
Peptides having pharmacological activity for treating disorders associated
with altered cell migration, such as cancer. Carriero, Maria Vincenza; De
Rosa, Mario; Pavone, Vincenzo. (Italy). PCT Int. Appl. (2008), 35pp.
CODEN: PIXXD2 WO 2008017372 A1 20080214 Designated States W: AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB,
GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM,
KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR,
TT, TZ. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB,
GR, IE, IS, IT, LU, MC, MT, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM,
GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application:
WO 2007-EP6424 20070719. Priority: IT 2006-1607 20060809. CAN 148:230115
AN 2008:192190
Patent Family Information
Patent No.
WO2008017372
Kind
A1
Date
20080214
Application No.
WO2007-EP6424
Date
20070719
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM,
KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG,
MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS,
IT, LT, LU, LV, MC, MT, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ, CF,
CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY,
KG, KZ, MD, RU, TJ, TM
Priority Application
IT2006-MI1607
A
20060809
Abstract: Peptides and their functionally equiv. derivs. are disclosed, in salified or
non-salified form, with the general formula L1-X1-X2-X3-X4, wherein: L1 is H, or
acyl, or any natural or non-natural amino acid, optionally N-acylated, N-alkylated
37
and/or Cα-alkylated; X1 and X3, which are equal or different, are any natural or
non-natural basic amino acid, optionally N-alkylated and/or Cα-alkylated. X2 is
any natural or non-natural amino acid, optionally N-alkylated and/or Cαalkylated, with the proviso that it is not glycine and amino acids mono-substituted
on the α carbon atom with a linear or cyclic alkyl group, from 1 to 10 carbon
atoms, and amino acids mono-substituted on the α carbon atom with a linear or
cyclic alkyl group contg. 4 to 10 carbon atoms, or amino acids mono-substituted on
the α carbon atom with an alkyl group contg. 1 to 8 carbon atoms, optionally
substituted with a carbamoyl, hydroxyl or arom. group; X4 is any natural or nonnatural hydrophobic amino acid, optionally Cα-alkylated and/or amidated at the
C-terminal end, or any hydrophobic amino alc., or a hydrophobic gem-diamine,
optionally N'-alkylated or N'-acylated.
2.
RANTES-derived peptides for treatment of diseases involving RANTES
receptors. Pavone, Vincenzo; Lusso, Paolo. (Primm S.R.L., Italy). PCT Int.
Appl. (2004), 18 pp. CODEN: PIXXD2 WO 2004065406 A2 20040805
Designated States W: AE. Patent written in English. Application: WO 2004IB155 20040122. Priority: IT 2003-107 20030124. CAN 141:167845 AN 2004:633944
Patent No.
WO2004065406
WO2004065406
Kind
A2
A3
Date
20040805
20040916
Application No.
WO2004-IB155
Date
20040122
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH,
CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD,
GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI
Patent No.
EP1585764
Kind
A2
Date
20051019
Application No.
EP2004-704297
Date
20040122
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI,
LT, LV, FI, RO, MK, CY, AL, TR, BG, CZ, EE, HU, SK
Patent No.
US20060165650
Kind
A1
IT2003-MI107
A
WO2004-IB155
W
Date
20060727
Application No.
US2005-542857
Date
20050721
20030124
20040122
38
Abstract: This invention describes the prepn. of RANTES-derived peptides of
general formula Ac-C-x1-PYI-x2-x3-Y-NH2 (x1, x3 = Phe, Tyr, Nal, Cha; x2 =
spacer of 2 to 12 amino acidic residues) for treatment of diseases in which
RANTES receptor is involved. Peptides of the invention are useful for prevention
or treatment of AIDS and other viral diseases, inflammatory, allergic,
degenerative, and neoplastic diseases and all diseases in which chemokines or
their receptors are involved.
3.
New cyclic peptides, their preparation and pharmaceutical use as
immunosuppressants. Lombardi, Angelina; Pavone, Vincenzo. (Universita'
degli Studi di Napoli Federico II, Italy). Ital. Appl. (2002), 51pp. CODEN:
ITXXCZ IT 2001RM0285 A1 20021128 Patent written in Italian. Application:
IT 2001-285 20010528. Priority: . CAN 146:380315 AN 2007:413297
Patent No.
IT2001RM0285
Kind
A1
IT2001-RM285
Date
20021128
Application No.
IT2001-RM285
Date
20010528
20010528
Abstract: Cyclic peptides cyclo[X1-X2-X3-X4-X5-X6] and cyclo[Y6-Y5-Y4-Y3Y2-Y1] [X1, X2 = independently hydrophobic natural or synthetic L-amino acid;
X3, X5 = independently hydrophilic natural or synthetic L-amino acid or Gly; X4,
Y4 = independently natural or synthetic D-amino acid or Gly, or αmethylalanine, α-aminocyclobutanecarboxylic acid, etc.; X6, Y6 = independently
natural or synthetic L-amino acid or Gly, or α-methylalanine, αaminocyclobutanecarboxylic acid, etc.; Y1, Y2 = independently hydrophobic
natural or synthetic D-amino acid; Y3, Y5 = independently hydrophilic natural or
synthetic D-amino acid or Gly] were prepd. as immunosuppressants useful for
treating pathologies involving activation of T-lymphocytes. Their
immunosuppressant activity was detd. in vitro and in vivo in human or murine
mixed lymphocyte cultures by measuring lymphocyte proliferation by [3H]-TdR
incorporation assay and the prodn. of interferon γ and interleukin-5 by ELISA
assay. Thus, cyclo[(β-1-Nal)-(β-1-Nal)-Glu-(D-Pro)-His-Asn] (β-1-Nal = β-1naphthylalanine), prepd. by a solid phase synthesis, significantly decreased
lymphocyte proliferation and inhibited prodn. of interferon γ and interleukin-5.
4.
Pseudo-metalloproteins, their preparation and use in biosensors. Lombardi,
Angelina; Pavone, Vincenzo. (Universita' Degli Studi di Napoli "Federico
II", Italy). PCT Int. Appl. (2002), 22 pp. CODEN: PIXXD2 WO 2002012278
A2 20020214 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB,
39
BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC,
EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW, AM, AZ, BY, KG, KZ, MD,
RU, TJ, TM. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR,
GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA,
ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO
2001-IB1427 20010809. Priority: IT 2000-454 20000810. CAN 136:180121 AN
2002:123042
Patent No.
WO2002012278
WO2002012278
Kind
A2
A3
Date
20020214
20020613
Application No.
WO2001-IB1427
Date
20010809
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM,
HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU,
SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU,
ZA, ZW
RW: GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW, AT, BE, CH, CY,
DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF,
CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG
Patent No.
IT2000RM0454
IT1317895
CA2419019
AU2001076606
EP1309612
Kind
A1
B1
A1
A
A2
Date
20020211
20030715
20020214
20020218
20030514
Application No.
IT2000-RM454
Date
20000810
CA2001-2419019
AU2001-76606
EP2001-954265
20010809
20010809
20010809
LT, LV, FI, RO, MK, CY, AL, TR
Patent No.
NZ524643
AU2001276606
US20050090649
Kind
A
B2
A1
Date
20040924
20070118
20050428
Application No.
NZ2001-524643
AU2001-276606
US2003-344329
Date
20010809
20010809
20030731
40
IT2000-RM454
A
WO2001-IB1427
W
20000810
20010809
Abstract: Described herein are Pseudo-metalloproteins (M = metal selected among
Fe, Mn, Ti, Mo, Co, Ni, Cu, Pd, Pt, Au, Ru, Cr, V, Tb, Yb, Rh, Ir, Os; X1 =
antigen, or else a functional group that enables assocn. to a biomol.; X2 =
functional group that enables assocn. to an electrode; S1 and S2 = spacer groups
made up of a chain of 3-12 atoms of C, N, O, S and corresponding mixts.; all the
other substituents have an amino acid nature), their prepn., and electrochem.
biosensors contg. them. The biosensors can be used in various assays such as
diagnostic assays, immunodiagnostic assays, detn. of pollutants in water, etc. A
peptide-metal complex, contg. Fe3+ as M; substance P sequence as X1; Cys as X2
and C1-4; Gly-Gly as S1 and S2, was prepd. The peptides were synthesized on an
automatic peptide synthesizer and then complexed with Fe(SO4)2(NH4)2.
5.
RANTES-derived peptides with anti-HIV, anti-allergic, and antiinflammatory activity. Lusso, Paolo; Pavone, Vincenzo. (Fondazione Centro
San Raffaele del Monte Tabor, Italy; Primm S.R.L.). PCT Int. Appl. (2000),
23 pp. CODEN: PIXXD2 WO 2000027880 A2 20000518 Designated States W:
AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU,
CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN,
IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG,
MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW, AM, AZ, BY,
KG, KZ, MD, RU, TJ, TM. Designated States RW: AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, BF, BJ, CF, CG, CI,
CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English.
Application: WO 99-EP8651 19991111. Priority: IT 98-2441 19981111. CAN
133:824 AN 2000:335443
Patent No.
WO2000027880
WO2000027880
Kind
A2
A3
Date
20000518
20001005
Application No.
WO1999-EP8651
Date
19991111
W: AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU,
CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN,
IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG,
MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW
41
RW: GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW, AT, BE, CH, CY, DE,
DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, BF, BJ, CF, CG, CI,
CM, GA, GN, GW, ML, MR, NE, SN, TD, TG
Patent No.
IT98MI2441
IT1303736
CA2348308
EP1131352
Kind
A1
B1
A1
A2
Date
20000511
20010223
20000518
20010912
Application No.
IT1998-MI2441
Date
19981111
CA1999-2348308
EP1999-968785
19991111
19991111
LT, LV, FI, RO
Patent No.
JP2003500334
US6709649
Kind
T
B1
IT1998-MI2441
A
WO1999-EP8651 W
Date
20030107
20040323
Application No.
JP2000-581057
US2001-831500
Date
19991111
20010622
19981111
19991111
Abstract: Peptides are provided which have 12-30 amino acids with a sequence
homologous or corresponding to the sequence 10-34 of RANTES and have
inhibitory activity against the human immunodeficiency virus (HIV) as well as
anti-allergic and anti-inflammatory activity.
6.
Preparation of soluble peptide tachykinin antagonists. Pavone, Vincenzo;
Lombardi, Angelina; Pedone, Carlo; De Rosa, Mario; Rossi, Mose. (Centro
Interuniversitario Di Ricerca Sui Peptidi Bioattivi-Universita Degli, Italy).
PCT Int. Appl. (1997), 15 pp. CODEN: PIXXD2 WO 9731941 A2 19970904
Designated States W: AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA,
CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA,
UG, US, UZ, VN, YU, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM.
Designated States RW: AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT,
LU, MC, NL, PT, SE, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD,
TG. Patent written in English. Application: WO 97-EP917 19970226. Priority:
IT 96-1401 19960301. CAN 127:248426 AN 1997:594751
Patent No.
Kind
Date
Application No.
Date
42
WO9731941
WO9731941
A2
A3
19970904
19971023
WO1997-EP917
19970226
W: AL, AM, AT, AU, AZ, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK,
EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
LS, LT, LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU
RW: GH, KE, LS, MW, SD, SZ, UG, AT, BE, CH, DE, DK, ES, FI, FR, GB,
GR, IE, IT, LU, MC, NL, PT, SE, BF, BJ, CF, CG, CI, CM, GA, GN, ML,
MR, NE, SN, TD, TG
Patent No.
CA2247802
AU9718771
EP894093
EP894093
Kind
A1
A
A2
B1
Date
19970904
19970916
19990203
20020522
Application No.
CA1997-2247802
AU1997-18771
EP1997-905089
Date
19970226
19970226
19970226
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, F
Patent No.
JP2001502656
AT217886
US6075006
Kind
T
T
A
IT1996-MI401
A
WO1997-EP917
W
Date
20010227
20020615
20000613
Application No.
JP1997-530587
AT1997-905089
US1998-125542
Date
19970226
19970226
19980828
19960301
19970226
Abstract: Glycosated cyclopeptides I [X1 = D- or L-Cys(Y), D- or L-SeCys(Y); Z1
= Asp, Z2 = Dap; Z1 = Dap, Z2 = Asp; X2, X3, X4 = natural or synthetic
hydrophobic amino acids, having Z1, Z2, X2, X3, and X4 the same D- or Lconfiguration; Y = glycosidic group selected from the aldo and keto hexoses in the
furanose or pyranose form bound to the Cys residue with an α- or β- thioacetal
bond or a cyclitol or a polyvinyl alc. or PEG group contg. 5-10 monomers, bound
to the Cys with a thioether bond; SeCys = selenocysteine; Dap = 2,3diaminopropanoic acid], are endowed of high soly. and of potent tachykininantagonistic activity. Thus, galactocysteine cyclopeptide II, prepd. by std. solidphase methods, inhibited neurokinin A response to an agonist with pA2 = 8.4 and
had a soly. of 1.8 µg/mL.
43
X 1 - Z 1 -X 2 -X 3 -Z 2 -X 4
H-C ys-A sp-Trp-Phe-D
OH
O
I
ap-Leu-OH
OH
HO
HO
7.
II
Preparation of cyclic peptide tachykinin antagonists. Pavone, Vincenzo;
Lombardi, Angelina; Pedone, Carlo; Maggi, Carlo Alberto; Quartara, Laura.
(Menarini A., Industrie Farmaceutiche Riunite S.r.L., Italy; Laboratori
Guidotti S.p.A.; Malesci - Istituto Farmacobiologico S.p.A.). PCT Int. Appl.
(1993), 29 pp. CODEN: PIXXD2 WO 9321227 A1 19931028 Designated States
W: AU, BB, BG, BR, CA, CZ, FI, HU, JP, KP, KR, KZ, LK, MG, MN, MW,
NO, NZ, PL, RO, RU, SD, SK, UA, US, VN. Designated States RW: AT,
BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, BF, BJ,
CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in
English. Application: WO 93-EP893 19930413. Priority: IT 92-89 19920415.
CAN 121:158200 AN 1994:558200
Patent No.
WO9321227
Kind
A1
Date
19931028
Application No.
WO1993-EP893
Date
19930413
W: AU, BB, BG, BR, CA, CZ, FI, HU, JP, KP, KR, KZ, LK, MG, MN, MW,
NO, NZ, PL, RO, RU, SD, SK, UA, US, VN
RW: AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, BF,
BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG
Patent No.
AU9340395
AU671118
EP636146
EP636146
Kind
A
B2
A1
B1
Date
19931118
19960815
19950201
19970730
Application No.
AU1993-40395
Date
19930413
EP1993-911459
19930413
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LI, LU, MC, NL, PT, SE
Patent No.
HU70189
JP08500331
IN177038
Kind
A2
T
A1
Date
19950928
19960116
19961026
Application No.
HU1994-2977
JP1993-517974
IN1993-CA212
Date
19930413
19930413
19930413
44
AT156135
ES2105265
RO112872
BR9306248
CN1080916
CN1039126
IL105381
ZA9302644
NO9403861
FI9404838
IN1995CA00332
US5731285
T
T3
B1
A
A
B
A
A
A
A
A
A
19970815
19971016
19980130
19980623
19940119
19980715
19980222
19931022
19941013
19941014
20050304
19980324
IT1992-FI89
A
WO1993-EP893
A
US1994-318669
B1
AT1993-911459
ES1993-911459
RO1994-1666
BR1993-6248
CN1993-104453
19930413
19930413
19930413
19930413
19930414
IL1993-105381
ZA1993-2644
NO1994-3861
FI1994-4838
IN1995-CA332
US1996-731709
19930414
19930415
19941013
19941014
19950327
19961017
19920415
19930413
19941006
Abstract: Title compds. (I; X1-X6 = NR'CO, CONR'; R, R' = H, alkyl; Y =
CONR, NRCO, OCO, COO, CH2R, NRCH2, SS, CH2CH2, CH:CH; R1-R4 =
hydrophobic group; n, m = 1-4), were prepd. Thus, title compd. II (Dpr = 2,3diaminopropionyl residue), prepd. via cyclization of intermediate III using
PyBOP/DIEA in DMF, at 10 µM gave 100% inhibition of response to substance P
Me ester by isolated guinea pig ileum.
R 1 CH
X2
CH
X3
CHR 2
CH 2 ) n
X1
X4
Y
CH 2 ) m
R 4 CH
X6
CH
X5
CHR 3
H-Met-A sp-Trp-Phe-D
I
Met-A sp-Trp-Phe-D
pr-Leu-OH
pr-L eu
II
III
45
PUBBLICAZIONI
1.
An urokinase receptor antagonist that inhibits cell migration by blocking
the formyl peptide receptor. Bifulco, Katia; Longanesi-Cattani, Immacolata;
Gargiulo, Lucia; Maglio, Ornella; Cataldi, Mauro; De Rosa, Mario;
Stoppelli, Maria Patrizia; Pavone, Vincenzo; Carriero, Maria Vincenza.
FEBS Letters (2008), 582(7), 1141-1146.
Abstract: Urokinase receptor (uPAR) plays a key role in physiol. and pathol.
processes sustained by an altered cell migration. We have developed
peptides carrying amino acid substitutions along the Ser88-Arg-Ser-ArgTyr92 (SRSRY) uPAR chemotactic sequence. The peptide pyro glutamic
acid (pGlu)-Arg-Glu-Arg-Tyr-NH2 (pERERY-NH2) shares the same
binding site with SRSRY and competes with N-formyl-Met-Leu-Phe
(fMLF) for binding to the G-protein-coupled N-formyl-peptide receptor
(FPR). pERERY-NH2 is a dose-dependent inhibitor of both SRSRY- and
fMLF-directed cell migration, and prevents agonist-induced FPR
internalization and fMLF-dependent ERK1/2 phosphorylation. pERERYNH2 is a new and potent uPAR inhibitor which may suggest the generation
of new pharmacol. treatments for pathol. conditions involving increased cell
migration.
2.
Critical role of the N-loop and β1-strand hydrophobic clusters of RANTESderived peptides in anti-HIV activity. Vangelista, Luca; Longhi, Renato;
Sironi, Francesca; Pavone, Vincenzo; Lusso, Paolo. Biochemical and
Biophysical Research Communications (2006), 351(3), 664-668.
Abstract: HIV initiates its infectious cycle by docking to CD4 and a
chemokine receptor, most commonly CCR5. RANTES, a natural CCR5
ligand, is a potent inhibitor of HIV-1. Despite the lack of structural
information on the RANTES-CCR5 complex, determinants of HIV
blockade were previously identified within the RANTES N-loop and β1strand regions. A prototype N-loop/β1-strand peptide, named R11-29,
contains two terminal hydrophobic stretches sepd. by a central hydrophilic
region. Here, the role of the terminal hydrophobic clusters was investigated
by means of amino acid substitutions or deletions. Most hydrophobic
residues in these clusters were shown to be fundamental for the anti-HIV
activity. However, increasing the hydrophobicity of the two clusters using
non-natural amino acids did not significantly improve the potency of the
peptides. These results may provide instrumental knowledge for the
rational design of RANTES-deriv. mols. with increased anti-HIV activity.
3.
Artificial di-iron proteins: solution characterization of four helix bundles
46
containing two distinct types of inter-helical loops. Maglio, Ornella; Nastri,
Flavia; Calhoun, Jennifer R.; Lahr, Stephen; Wade, Herschel; Pavone,
Vincenzo; DeGrado, William F.; Lombardi, Angela. JBIC, Journal of
Biological Inorganic Chemistry (2005), 10(5), 539-549.
Abstract: Peptide-based models have an enormous impact for the
development of metalloprotein models, as they seem appropriate candidates
to mimic both the structural characteristics and reactivity of the natural
systems. Through the de novo design of four-helix bundles, we developed
the DF (Due Ferri) family of artificial proteins, as models of di-iron and dimanganese metalloproteins. The goal of our research is to elucidate how the
electrostatic environment, polarity and solvent accessibility of the metalbinding site, influence the functional properties of di-iron proteins. The
first two subsets of the DF protein family, DF1 and DF2, consist of two
non-covalently assocd. helix-loop-helix motifs, which bind the di-metal
cofactor near the center of the structure. The DF2 subset was designed to
improve the properties of DF1: DF2 and DF2t have several changes in their
sequences to improve soly. and metal ion access, as well as a change in the
loop connecting the two helixes. In order to evaluate how these changes
affect the overall structure of the model proteins, we solved the NMR
structures of the di-Zn(II) complexes of DF2 and DF2t, and compared these
structures with those recently obtained from X-ray crystallog. Further, we
examd. the thermodn. consequences assocd. with the mutations, by
measuring the stability of DF2t in the presence of different metal ions, and
comparing the results with the data already obtained for DF2. Taken
together, anal. of all the data showed the importance of the turn
conformation in the design and stability of four-helix bundle.
4.
Miniaturized heme proteins: crystal structure of Co(III)-mimochrome IV.
Costanzo, Luigi; Geremia, Silvano; Randaccio, Lucio; Nastri, Flavia;
Maglio, Ornella; Lombardi, Angela; Pavone, Vincenzo. JBIC, Journal of
Biological Inorganic Chemistry (2004), 9(8), 1017-1027.
Abstract: Protein design provides an attractive approach to test the essential
features required for folding and function. Previously, we described the
design and structural characterization in soln. of mimochromes, a series of
miniaturized metalloproteins, patterned after the F-helix of the Hb β-chain.
Mimochromes consist of two medium-sized helical peptides, covalently
linked to the deuteroporphyrin. CD and NMR characterization of the
prototype, mimochrome I, revealed that the overall structure conforms well
to the design. However, formation of ∆ and Λ diastereomers was obsd. To
overcome the problem of diastereomer formation, we re-designed
mimochrome I, by engineering intramol., interchain interactions. The
47
resulting model was mimochrome IV: the soln. structural characterization
showed the presence of the Λ isomer as a unique form. To examine the
extent to which the stereochem. stability and uniqueness of mimochrome
IV was retained in the solid state, the crystal structure of Co(III)mimochrome IV was solved by x-ray diffraction, and compared to the soln.
structure of the same deriv. Co(III)-mimochrome IV structures, both in
soln. and in the solid state, are characterized by the following common
features: a bis-His axial coordination, a Λ configuration around the metal
ion, and a predominant helical conformation of the peptide chains.
However, in the crystal structure, intrachain Glu1-Arg9 ion pairs are
preferred over the designed, and exptl. found in soln., interchain
interactions. This ion pairing switch may be related to strong packing
interactions.
5.
Design of a new mimochrome with unique topology. Lombardi, Angela;
Nastri, Flavia; Marasco, Daniela; Maglio, Ornella; De Sanctis, Giampiero;
Sinibaldi, Federica; Santucci, Roberto; Coletta, Massimo; Pavone,
Vincenzo. Chemistry -A European Journal (2003), 9(22), 5643-5654.
Abstract: Peptide-based metalloprotein models represent useful systems to
help understand how metalloproteins can support different functions, using
similar metal ion cofactors. To shed light on the role of the protein matrix
in modulating the heme properties, the authors developed new models:
mimochromes. They are pseudo-C2 sym. systems, composed of two helical
peptides covalently linked to the deuteroporphyrin. The use of C2
symmetry is particularly advantageous, because it simplifies the design,
synthesis and characterization. However, it leaves the problem of possible
diastereomeric forms. In the cobalt complex of the first deriv., mimochrome
I, Λ and ∆ isomers were indeed exptl. obsd. All the insights derived from
the CoIII-mimochrome I structure were used to obtain a re-designed mol.,
mimochrome IV. The spectroscopic characterization of the iron and cobalt
derivs. suggested the Λ isomer as unique species. The NMR soln. structure
of the diamagnetic CoIII-mimochrome IV confirmed the ability of the mol.
to adopt a unique topol., and revealed the peptide chains to be in helical
conformation, as designed. The insertion of intramol., inter-chain
interactions was successful in favoring the formation of one of the two
possible diastereomers. The stereochem. stable structure of mimochrome IV
provides an attractive model for modulating the redox potential of the
heme, by simple changing the peptide chain compn. around the heme.
6.
Preorganization of molecular binding sites in designed diiron proteins.
Maglio, Ornella; Nastri, Flavia; Pavone, Vincenzo; Lombardi, Angela;
DeGrado, William F. Proceedings of the National Academy of Sciences of the
48
United States of America (2003), 100(7), 3772-3777.
Abstract: De novo protein design provides an attractive approach to
critically test the features that are required for metalloprotein structure and
function. Previously we designed and crystallog. characterized an idealized
dimeric model for the four-helix bundle class of diiron and dimanganese
proteins [Dueferri 1 (DF1)]. Although the protein bound metal ions in the
expected manner, access to its active site was blocked by large bulky
hydrophobic residues. Subsequently, a substrate-access channel was
introduced proximal to the metal-binding center, resulting in a protein with
properties more closely resembling those of natural enzymes. Here we
delineate the energetic and structural consequences assocd. with the
introduction of these binding sites. To det. the extent to which the binding
site was preorganized in the absence of metal ions, the apo structure of DF1
in soln. was solved by NMR and compared with the crystal structure of the
di-Zn(II) deriv. The overall fold of the apo protein was highly similar to
that of the di-Zn(II) deriv., although there was a rotation of one of the
helixes. We also examd. the thermodn. consequences assocd. with building
a small mol.-binding site within the protein. The protein exists in an equil.
between folded dimers and unfolded monomers. DF1 is a highly stable
protein (Kdiss = 0.001 fM), but the dissocn. const. increases to 0.6 nM (∆∆G
= 5.4 kcal/mol monomer) as the active-site cavity is increased to
accommodate small mols.
7.
Conformational and coordination properties of a peptide containing the
novel α,α-bis(2-pyridyl)glycine amino acid. Di Costanzo, Luigi; Geremia,
Silvano; Randaccio, Lucio; Ichino, Tomoyuki; Yanagihara, Ryoji; Yamada,
Takashi; Marasco, Daniela; Lombardi, Angela; Pavone, Vincenzo. Dalton
Transactions (2003), (5), 787-792.
Abstract: A fully protected tripeptide contg. a novel Cα,α-disubstituted
glycine-α,α-di(2-pyridyl)glycine (2Dpy)-in the central position and Cα,αdimethylglycine (Aib) in positions 1 and 3 was synthesized and structurally
characterized by single crystal x-ray anal. The 2Dpy residue bears two 2pyridyl moieties, which may coordinate metal ions, and promote selfassembly of peptide units. The tripeptide Z-Aib1-2Dpy2-Aib3-OCH3 (Z:
benzyloxycarbonyl) adopts in the solid state a folded type III (III') β-turn
conformation (with Aib1-2Dpy2 as corner residues), stabilized by an i ← i +
3 H bond between the Aib3 NH and the urethane CO group. The peptide
was able to self-assemble in the presence of Cu(II) ions, giving rise to an
octahedral complex with a 2 : 1 peptide/Cu(II) stoichiometry, which was
structurally characterized. The metal ion, arranged on a crystallog.
symmetry center, is coordinated by two symmetry related 2Dpy residues,
49
which act as tridentate ligands: each 2Dpy residue donates to the Cu(II) the
N atoms of both pyridyl moieties in the equatorial positions, and the
carbonyl O atom in the axial positions. A very similar folded conformation
characterizes the peptide in both the free and metal-bound states. The
overall peptide structure is ready to coordinate the metal ion without
substantial conformational changes. Metal binding of the tri-peptide toward
Cu ions was analyzed by UV-visible spectroscopy performed in MeOH
soln. The exptl. data agree with an equil. between two species in soln., one
in the ratio Cu/peptide 1:1, the other 1:2. The formation consts. are 9.7 × 103
M-1 and 3.5 × 102 M-1, resp. The molar absorptivities are 66 ± 3 M-1 cm-1
(590 nm) for the 2:1 complex and 17 ± 2 M-1 cm-1 (690 nm) for the other. All
the data obtained in the present work suggest that the 2Dpy residue is well
suited to be accommodated into folded conformations. The spontaneous
formation of an ordered structure by the 2Dpy contg. tri-peptide and Cu
ions may guide toward the design of more elaborate self-assembling
systems.
8.
Sliding helix and change of coordination geometry in a model Di-MnII
protein. DeGrado, William F.; Di Costanzo, Luigi; Geremia, Silvano;
Lombardi, Angela; Pavone, Vincenzo; Randaccio, Lucio. Angewandte
Chemie, International Edition (2003), 42(4), 417-420.
Abstract: A sliding helix mechanism for stabilizing a change in the ligand
environment of DF1, a model di-MnII protein is described. DF1 is a dimer
of helix loop motifs with a dimetal site near the center of the four-helixbundle structure. The DF1-L13G-DF1 has an active site cavity that has been
expanded by further reducing the bulk of residue 13 to Gly. The structure of
di-MnII-L13G-DF1 displays four crystallog. independent dimers in the
asym. unit. Anal. of the differences in crystal-lattice packing among the
four helix bundles revealed no significant relationship between the packing
environment and the different structural behavior of these mols.
9.
Toward the de novo design of a catalytically active helix bundle: A
substrate-accessible carboxylate-bridged dinuclear metal center. Di
Costanzo, Luigi; Wade, Herschel; Geremia, Silvano; Randaccio, Lucio;
Pavone, Vincenzo; DeGrado, William F.; Lombardi, Angela. Journal of the
American Chemical Society (2001), 123(51), 12749-12757.
Abstract: De novo design of proteins provides an attractive approach to
uncover the essential features required for their functions. Previously, the
authors described the design and crystal structure detn. of a di-Zn(II)
complex of "due-ferri-1" (DF1), a protein patterned after the diirondimanganese class of redox-active proteins. The overall structure of DF1,
50
which contains a carboxylate-bridged dinuclear metal site, agrees well with
the intended design. However, access to this dimetal site is blocked by a pair
of hydrophobic leucine residues (L13 and L13'), which prevent facile entry of
metal ions and small mols. The authors have now taken the next step in the
eventual construction of a catalytically active metalloenzyme by
engineering an active site cavity into DF1 through the replacement of these
two leucine residues with smaller residues. The crystal structure of the
dimanganous form of L13A-DF1 indeed shows a substrate access channel to
the dimetal center. In the crystal structure, water mols. and a ligating
DMSO mol., which forms a monat. bridge between the metal ions, occupy
the cavity. Furthermore, the diferric form of a deriv. of L13A-DF1, DF2, is
shown to bind azide, acetate, and small arom. mols.
10.
Calixarene-porphyrin supramolecular complexes: pH-tuning of the complex
stoichiometry. Di Costanzo, Luigi; Geremia, Silvano; Randaccio, Lucio;
Purrello, Roberto; Lauceri, Rosaria; Sciotto, Domenico; Gulino, Fabio
Giuseppe; Pavone, Vincenzo. Angewandte Chemie, International Edition
(2001), 40(22), 4245-4247.
Abstract: The formation of stable supramol. complexes, both in solid state
and in aq. soln., from the cationic porphyrin and the anionic sulfonated
calixarene (C4TsTc) blocked in a cone conformation and bearing carboxylic
functions is described. The supramol. complexes were prepd. and crystd. by
vapor-diffusion with hanging drops at 18 °C by using Linbro multiwell
tissue plates as containers for the reservoir soln. Single crystals of
porphyrin-calixarene complexes were obtained at pH 2 and pH 6. The
central H2T4 unit of a trimeric H2T4 ensemble was arranged on a
crystallog. center of symmetry and each of its methylpyridinium moieties
was inserted into a tetra-anionic C4TsTc mol. from the sulfonated side of
the calixarene. The crystals' asym. unit at pH 6 contained two heptaanionic calixarene mols., three tetracationic porphyrin rings, and two
sodium ions, with a H2T4:(C4TsTc+H2T4) molar ratio of 0.6. The
organization of cationic porphyrin was obtained due to the presence of
sulfonated and carboxylate groups on the upper and lower rim, resp.
11.
Structural determinants of CCR5 recognition and HIV-1 blockade in
RANTES. Nardese, Vanessa; Longhi, Renato; Polo, Simona; Sironi,
Francesca; Arcelloni, Cinzia; Paroni, Rita; DeSantis, Claudio; Sarmientos,
Paolo; Rizzi, Menico; Bolognesi, Martino; Pavone, Vincenzo; Lusso, Paolo.
Nature Structural Biology (2001), 8(7), 611-615.
Abstract: Certain chemokines act as natural antagonists of human
immunodeficiency virus (HIV) by blocking key viral coreceptors, such as
51
CCR5 and CXCR4, on the surface of susceptible cells. Elucidating the
structural determinants of the receptor-binding and HIV-inhibitory
functions of these chemokines is essential for the rational design of deriv.
mols. of therapeutic value. Here the authors identify the structural
determinants of CCR5 recognition and antiviral activity of the CC
chemokine RANTES, showing that crit. residues form a solvent-exposed
hydrophobic patch on the surface of the mol. Moreover, the authors
demonstrate that the biol. function is critically dependent on dimerization,
resulting in the exposure of a large (.apprx.180 .ANG.2), continuous
hydrophobic surface. Relevant to the development of novel therapeutic
approaches, the authors designed a retro inverted RANTES peptide
mimetic that maintained both HIV- and chemotaxis-antagonistic functions.
12.
The crystal structure of Afc-containing peptides. Lombardi, Angela; De
Simone, Giuseppina; Galdiero, Stefania; Nastri, Flavia; Di Costanzo, Luigi;
Makihira, Kazunari; Yamada, Takashi; Pavone, Vincenzo. Biopolymers
(2000), 53(2), 150-160.
Abstract: A systematic structural anal. of Afc (9-amino-fluorene-9carboxylic acid) contg. peptides is reported. The crystal structures of four
fully protected tripeptides Cbz-X-Afc-Y-OMe, (peptide a: X = Y = Gly;
peptide b: X = Aib, Y = Gly; peptide c: X = Gly, Y = Aib; peptide d: X = Y =
Aib; Aib = Cα,α-dimethylglycine; Cbz = benzyloxycarbonyl) have been
solved by x-ray crystallog. All the results suggest that the Afc residue has a
high propensity to assume an extended conformation. In fact, the Afc
residue adopts an extended conformation in peptides a-c. In contrast, Afc is
found in a folded conformation in the 310-helical region only for peptide d,
in which it is both preceded and followed by the strong helix promoting
Aib.
13.
Conformational behavior of Cα,α-diphenyl glycine: extended conformation
in tripeptides containing consecutive Dϕg residues. Pavone, Vincenzo;
Lombardi, Angela; Saviano, Michele; De Simone, Giuseppina; Nastri,
Flavia; Maglio, Ornella; Omote, Yuichiro; Yamanaka, Yoshinori; Yamada,
Takashi. Biopolymers (2000), 53(2), 161-168.
Abstract: Recent studies on the conformational preferences of the Dϕg
(Cα,α-diphenylglycine) residue showed that this Cα,α-disubstituted
glycine has a structural versatility. Dϕg can assume either folded or
extended conformations depending on the nature of the following or
preceding residue. The conformational preferences of the Dϕg residue in
tripeptides contg. consecutive Dϕg residues are analyzed. The crystal
structures of Z-Dϕg-Dϕg-Dϕg-OMe (Z = benzyloxycarbonyl), Z-Aib-
52
Dϕg-Dϕg-OMe (Aib = α-aminoisobutyric acid), and Z-Ac3c-Dϕg-DϕgOMe (Ac3c = α-aminocyclopropanecarboxylic acid), are reported. The Dϕg
residues adopt the fully extended conformation in the three tripeptides
examd. Both previous and current data indicate that the presence of adjacent
Dϕg residue in the peptide further stabilizes the extended conformation.
14.
The crystal structure of a Dcp-containing peptide. De Simone, Giuseppina;
Lombardi, Angela; Galdiero, Stefania; Nastri, Flavia; Di Costanzo, Luigi;
Gohda, Shin; Sano, Atsuiro; Yamada, Takashi; Pavone, Vincenzo.
Biopolymers (2000), 53(2), 182-188.
Abstract: The conformational preferences of a newly synthesized Cα,α sym.
disubstituted glycine, α,α-dicyclopropylglycine (Dcp), have been
investigated. The crystal structure of a fully protected dipeptide contg. Dcp,
namely Z-Dcp1-Dcp2-OCH3 (Z = benzyloxycarbonyl) is reported. Both
Dcp residues are in a folded conformation. The overall peptide structural
organization corresponds to an α-pleated sheet conformation, similar to that
obsd. in linear peptides made up of alternating D- and L-residues and in ZAib-Aib-OCH3 (Aib = α,α-dimethylglycine). These preliminary data
suggest that the Dcp could represent an alternative as mol. tool to stabilize
folded conformations.
15.
Retrostructural analysis of metalloproteins: application to the design of a
minimal model for diiron proteins. Lombardi, Angela; Summa, Christopher
M.; Geremia, Silvano; Randaccio, Lucio; Pavone, Vincenzo; DeGrado,
William F. Proceedings of the National Academy of Sciences of the United States
of America (2000), 97(12), 6298-6305.
Abstract: De novo protein design provides an attractive approach for the
construction of models to probe the features required for function of
complex metalloproteins. The metal-binding sites of many metalloproteins
lie between multiple elements of secondary structure, inviting a
retrostructural approach to constructing minimal models of their active
sites. The backbone geometries comprising the metal-binding sites of zinc
fingers, diiron proteins, and rubredoxins may be described to within approx.
1 .ANG. rms deviation by using a simple geometric model with only six
adjustable parameters. These geometric models provide excellent starting
points for the design of metalloproteins, as illustrated in the construction of
Due Ferro 1 (DF1), a minimal model for the Glu-Xxx-Xxx-His class of
dinuclear metalloproteins. This protein was synthesized and structurally
characterized as the di-Zn(II) complex by x-ray crystallog., by using data
that extend to 2.5 .ANG.. This four-helix bundle protein is comprised of
two noncovalently assocd. helix-loop-helix motifs. The dinuclear center
53
is formed by two bridging Glu and two chelating Glu side chains, as well as
two monodentate His ligands. The primary ligands are mostly buried in the
protein interior, and their geometries are stabilized by a network of
hydrogen bonds to second-shell ligands. In particular, a Tyr residue forms a
hydrogen bond to a chelating Glu ligand, similar to a motif found in the
diiron-contg. R2 subunit of Escherichia coli ribonucleotide reductase and the
ferritins. DF1 also binds cobalt and iron ions and should provide an
attractive model for a variety of diiron proteins that use oxygen for
processes including iron storage, radical formation, and hydrocarbon oxidn.
16.
Miniaturized metalloproteins: application to iron-sulfur proteins. Lombardi,
Angela; Marasco, Daniela; Maglio, Ornella; Di Costanzo, Luigi; Nastri,
Flavia; Pavone, Vincenzo. Proceedings of the National Academy of Sciences of
the United States of America (2000), 97(22), 11922-11927.
Abstract: The miniaturization process applied to rubredoxins generated a
class of peptide-based metalloprotein models, named METP (miniaturized
electron transfer protein). The crystal structure of Desulfovibrio vulgaris
rubredoxin was selected as a template for the construction of a tetrahedral
(Sγ-Cys)4 iron-binding site. Anal. of the structure showed that a sphere of
17 .ANG. in diam., centered on the metal, circumscribes two unconnected
approx. C2 symmetry related β-hairpins, each contg. the -Cys-(Aaa)2-Cyssequence. These observations provided a starting point for the design of an
undecapeptide, which self assembles in the presence of tetrahedrally
coordinating metal ions. The METP peptide was synthesized in good yield
by std. methodologies. Successful assembly of the METP peptide with
Co(II), Zn(II), Fe(II/III), in the expected 2:1 stoichiometry, was proven by
UV-visible and CD spectroscopies. UV-visible anal. of the metal complexes
indicated the four Cys ligands tetrahedrally arrange around the metal ion, as
designed. CD measurements on both the free and metal-bound forms
revealed that the metal coordination drives the peptide chain to fold into a
turned conformation. NMR characterization of the Zn(II)-METP complex
fully supported the structure of the designed model. These results prove
that METP reproduces the main features of rubredoxin.
17.
Crystallization and preliminary x-ray diffraction studies of the
carboxylesterase EST2 from Alicyclobacillus acidocaldarius. De Simone,
Giuseppina; Manco, Giuseppe; Galdiero, Stefania; Lombardi, Angela; Rossi,
Mose; Pavone, Vincenzo. Acta Crystallographica, Section D: Biological
Crystallography (1999), D55(7), 1348-1349.
Abstract: EST2, a thermophilic carboxylesterase from A. acidocaldarius,
belonging to the HSL group of the esterase/lipase superfamily, was crystd.
54
for the 1st time. (NH4)2SO4 was used as a precipitant and the crystn.
proceeded at pH 7.8. The crystals belong to space group P41212 or its
enantiomorph P43212, with unit-cell parameters a = b = 78.8, c = 106.4
.ANG.. A complete data set was collected at the synchrotron source Elettra
in Trieste to 2.4 .ANG. resoln., using a single frozen crystal.
18.
Maroteaux-Lamy syndrome: five novel mutations and their structural
localization. Villani, G. R. D.; Balzano, N.; Vitale, D.; Saviano, M.; Pavone,
V.; Di Natale, P. Biochimica et Biophysica Acta, Molecular Basis of Disease
(1999), 1453(2), 185-192.
Abstract: Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI,
MPS VI) is an autosomal recessive disorder due to the deficiency of the
lysosomal enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B,
ASB). Mutation anal. in Maroteaux-Lamy syndrome resulted in the
identification of approx. 40 mol. defects underlying a great genetic
heterogeneity. Here the authors report five novel mutations in Italian
subjects: S65F, P116H, R315Q, Q503X, P531R; each defect was confirmed by
restriction enzyme or amplification refractory mutation system (ARMS)
anal. The authors also performed a three-dimensional (3-D) structure anal.
of the alterations identified by the authors', and of an addnl. 22 point
mutations reported by other groups, to draw helpful information about their
possible effects on protein conformation.
19.
The crystal structure of α-thrombin-hirunorm IV complex reveals a novel
specificity site recognition mode. Lombardi, Angela; De Simone,
Giuseppina; Nastri, Flavia; Galdiero, Stefania; Della Morte, Rossella;
Staiano, Norma; Pedone, Carlo; Bolognesi, Martino; Pavone, Vincenzo.
Protein Science (1999), 8(1), 91-95.
Abstract: The x-ray crystal structure of the human α-thrombin (I)hirunorm IV (II) complex was detd. at 2.5 .ANG. resoln., and refined to an
R-factor of 0.173. The structure revealed an inhibitor binding mode
distinctive of a true hirudin mimetic, which justified the high inhibitory
potency and the selectivity of II. This novel inhibitor, II, composed of 26
amino acids, interacted through the N-terminal end with the I active site in
a nonsubstrate mode, and bound specifically to the fibrinogen recognition
exosite through the C-terminal end. The backbone of the N-terminal
tripeptide, Chg-1"-Arg-2"-2Nal-3" [Chg = cyclohexylglycine; 2Nal = β-(2naphthyl)alanine] formed a parallel β-strand to the thrombin main-chain
segment, Ser-214-Gly-216. The Chg-1" side-chain occupied the S2 site, Arg-2"
penetrated into the S1 specificity site, whereas the 2Nal-3" side-chain
occupied the aryl binding site. The Arg-2" side-chain entered the S1
55
specificity pocket from a position quite apart from the canonical P1 site.
This notwithstanding, the Arg2" side-chain established the typical ion pair
with the carboxylate group of Asp-189.
20.
Hemoprotein models based on a covalent helix-heme-helix sandwich. 3.
Coordination properties, reactivity and catalytic application of Fe(III)- and
Fe(II)-mimochrome I. Nastri, Flavia; Lombardi, Angela; Morelli,
Giancarlo; Pedone, Carlo; Pavone, Vincenzo; Chottard, Genevieve;
Battioni, Pierrette; Mansuy, Daniel. JBIC, Journal of Biological Inorganic
Chemistry (1998), 3(6), 671-681.
Abstract: The coordination state of Fe(III)- and Fe(II)-mimochrome I, a
covalent peptide-deuteroheme sandwich involving two nonapeptides
bearing a histidine residue in a central position, was studied by UV-visible,
EPR, and resonance Raman spectroscopy. The ferric and ferrous states of
this new iron species mainly exist, at pH7, in a low-spin hexacoordinate
form with two axial histidine ligands coming from the peptide chains. A
minor amt. of high-spin form for the ferric state is also present at pH 7.
However, it is mainly high-spin at pH 2 or in DMSO. Fe(II)-mimochrome
I binds CO with an affinity comparable to that of myoglobin and Hb.
Fe(III)-mimochrome I reacts with alkylhydroxylamine and arylhydrazines,
leading to the corresponding Fe(II)-nitrosoalkyl and Fe(III)-σ-aryl
complexes, resp. These reactions were greatly dependent on the solvent
used and on the pH, and were much slower than the corresponding
reactions performed by deuterohemin in the presence of excess imidazole.
All these results indicate that the reactivity of iron-mimochrome I is
controlled by the binding of the peptide chains to the iron. The reactivity
shown by this complex at neutral pH is intermediate between that obsd. for
iron porphyrins in the presence of excess imidazole and that of
hemoproteins characterized by a strong bis-histidine axial coordination,
such as cytochrome b5. Fe(III)-mimochrome I is able to catalyze styrene
epoxidn. by using a [Fe(III)-mimochrome I]/[H2O2]/[styrene] ratio of
1:10:2000 in phosphate buffer soln. (pH 7.2) contg. 2% CTAB both under
strictly anaerobic conditions and in the presence of oxygen, at 0°C.
21.
Neuronorm is a potent and water soluble neurokinin A receptor antagonist.
Lombardi, Angela; D'agostino, Bruno; Filippelli, Amelia; Pedone, Carlo;
Matera, Maria Gabriella; Falciani, Maddalena; De Rosa, Mario; Rossi,
Francesco; Pavone, Vincenzo. Bioorganic & Medicinal Chemistry Letters
(1998), 8(13), 1735-1740.
Abstract: The authors report the synthesis and preliminary pharmacol.
characterization of a novel water sol. Neurokinin A (NKA) receptor
56
antagonist named Neuronorm, cyclo[Cys1(β-D-Gal)-Asp2-Trp3-Phe4Dap5-Leu6]cyclo(2β-5β). The synthesis was achieved in high yield by a
combination of classical peptide synthesis methodologies, in both soln. and
solid phase. The pharmacol. properties as neurokinin A receptor antagonist
were assessed in in vitro expts. on rat vas deferens and guinea pig trachea,
and were compared to those of MEN10627.
22.
A Novel Rigid β -Turn Molecular Scaffold. Lombardi, Angela; D'Auria,
Gabriella; Maglio, Ornella; Nastri, Flavia; Quartara, Laura; Pedone, Carlo;
Pavone, Vincenzo. Journal of the American Chemical Society (1998), 120(24),
5879-5886.
Abstract: We describe here the soln. 1H NMR anal., restrained and
unrestrained mol. dynamic simulations of the bicyclic peptide cyclo(Met1asp2-Trp3-Phe4-dap5-Leu6)cyclo(2β-5β) (MEN10701) [dap = (2R)-2,3diaminopropionic acid]. This compd. is an analog of cyclo(Met1-Asp2-Trp3Phe4-Dap5-Leu6)cyclo(2β-5β)
(MEN10627)
[Dap
=
(2S)-2,3diaminopropionic acid], which is the most potent and selective, peptidebased NK2 receptor antagonist known to date. MEN10701 differs from
MEN10627 in the D chirality of the Asp2 and Dap5 residues; it was designed
to better understand the role of the lactam bridge in detg. the shape of the
mol. and to elucidate whether its position, above or below the plane contg.
the pharmacophores (Met1, Trp3, Phe4, and Leu6 side chains), could
modulate the biol. response. Despite our expectations, the uncoercible
bicyclic structure of MEN10627 is dramatically coerced into a novel
conformation, by the replacement of the lactam bridge forming units (Asp2
and Dap5) with residues of opposite chirality. The overall shape of
MEN10701 is also quite unique because of its compactness. It is ellipsoidal
instead of being rectangle-like, and the structure is stabilized by two
intramol. hydrogen bonds encompassing two type I' β-turns. This structure
can be added to the repertoire of rigid β-turn scaffolds for the design of
bioactive mols., which require turned motifs to elicit potency and
specificity.
23.
Miniaturized hemoproteins: design, synthesis and characterization of
mimochrome II. Lombardi, Angela; Nastri, Flavia; Sanseverino, Marina;
Maglio, Ornella; Pedone, Carlo; Pavone, Vincenzo. Inorganica Chimica Acta
(1998), 275-276(1,2), 301-313.
Abstract: The present paper describes the design, synthesis and
spectroscopic characterization of mimochrome II, namely 3,7,12,17tetramethylporphyrin-2,18-di-N9.vepsiln.-(Ac-Asp1-Leu2-Ser3-Asp4-Leu5His6-Ser7-Lys8-Lys9-Leu10-Lys11-Ile12-Thr13-Leu14-NH2)
57
propionamide, and its cobalt deriv. Mimochrome II belongs to a new class
of hemoprotein models, called mimochromes. We have developed these
mols. in order to investigate the effect of protein structure and compn. on
modulation of the activity of the heme center. These mols. are composed of
two helical peptide chains linked covalently to the deuteroporphyrin IX.
The synthetic procedure we developed for synthesizing the prototype mol.
mimochrome I, together with the information derived from the structural
characterization of the Fe(III)- and Co(III)-mimochrome I complexes,
enabled us to design mols. having more precise properties. By comparing
the behavior of Co(III)-mimochrome II with that of the prototype mol.
mimochrome I, we show here that the compn. and folding of the peptide
chains affect critically the overall structural organization of the models.
24.
A novel super-potent neurokinin A receptor antagonist containing
dehydroalanine. Lombardi, Angela; D'agostino, Bruno; Nastri, Flavia;
D'andrea, Luca D.; Filippelli, Amelia; Falciani, Maddalena; Rossi,
Francesco; Pavone, Vincenzo. Bioorganic & Medicinal Chemistry Letters
(1998), 8(10), 1153-1156.
Abstract: The authors report the synthesis and preliminary pharmacol.
characterization of a novel Neurokinin A receptor antagonist. This peptide,
∆-Ala1-Neuronorm, contains a dehydroalanine residue; it displays a high
conformational rigidity and possesses very high activity. Its pharmacol.
properties as a neurokinin A receptor antagonist were assessed in in-vitro
expts. on rat vas deferens and were compared to those of Neuronorm and
MEN10627.
25.
Conformational behavior of Cα,α-diphenylglycine: folded vs. extended
structures in DΦg-containing tripeptides. Pavone, Vincenzo; Lombardi,
Angela; Saviano, Michele; Nastri, Flavia; Zaccaro, Laura; Maglio, Ornella;
Pedone, Carlo; Omote, Yuichiro; Yamanaka, Yoshinori; Yamada, Takashi.
Journal of Peptide Science (1998), 4(1), 21-32.
Abstract: The crystal structures of three fully protected tripeptides contg.
the DΦg residue (Cα,α-diphenylglycine) in the central position are
reported, namely Z-Gly-DΦg-Gly-OMe (a), Z-Gly-DΦg-Aib-OMe (b) and
Z-Aib-DΦg-Aib-OMe (c). The mol. conformations are quite unusual
because the DΦg residue adopts a folded conformation in the 310-helical
region when the following residue adopts a folded conformation of opposite
handedness (peptides b and c). In contrast, the DΦg residue adopts the more
frequently obsd. fully extended conformation when the following residue
adopts a semi-extended conformation (peptide a). These findings are in
agreement with the theor. calcns. on Ac-DΦg-Aib-NHCH3 and Ac-
58
Aib-DΦg-NHCH3 also reported in this work.
26.
Hirunorms are true hirudin mimetics. The crystal structure of human αthrombin-hirunorm V complex. De Simone, Giuseppina; Lombardi,
Angela; Galdiero, Stefania; Nastri, Flavia; Morte, Rossella Della; Staiano,
Norma; Pedone, Carlo; Bolognesi, Martino; Pavone, Vincenzo. Protein
Science (1998), 7(2), 243-253.
Abstract: A novel class of synthetic, multisite-directed thrombin inhibitors,
known as hirunorms, has been described recently. These compds. were
designed to mimic the binding mode of hirudin, and they have been proven
to be very strong and selective thrombin inhibitors. Here the authors report
the crystal structure of the complex formed by human α-thrombin and
hirunorm V, a 26-residue polypeptide contg. non-natural amino acids, detd.
at 2.1 .ANG. resoln. and refined to an R-factor of 0.176. The structure
reveals that the inhibitor binding mode is distinctive of a true hirudin
mimetic, and it highlights the mol. basis of the high inhibitory potency (Ki
is in the picomolar range) and the strong selectivity of hirunorm V.
Hirunorm V interacts through the N-terminal tetrapeptide with the
thrombin active site in a nonsubstrate mode; at the same time, this inhibitor
specifically binds through the C-terminal segment to the fibrinogen
recognition exosite. The backbone of the N-terminal tetrapeptide Chg1"Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, β-(2-naphthyl)alanine) forms a short β-strand parallel to thrombin main-chain residues
Ser214-Gly219. The Chg1" side chain fills the S2 subsite, Val2" is located at
the entrance of S1, whereas 2-Nal3" side chain occupies the aryl-binding site.
Such backbone orientation is very close to that obsd. for the N-terminal
residues of hirudin, and it is similar to that of the synthetic retro-binding
peptide BMS-183507, but it is opposite to the proposed binding mode of
fibrinogen and of small synthetic substrates. Hirunorm V C-terminal
segment binds to the fibrinogen recognition exosite, similarly to what is
obsd. for hirudin C-terminal tail and related compds. The linker
polypeptide segment connecting hirunorm V N-and C-terminal regions is
not observable in the electron d. maps. The crystallog. anal. proves the
correctness of the design and it provides a compelling proof on the
interaction mechanism for this novel class of high potency multisitedirected synthetic thrombin inhibitors.
27.
Hemoprotein models based on a covalent helix-heme-helix sandwich: 2.
Structural characterization of CoIIImimochrome I ∆ and Λ isomers.
D'Auria, Gabriella; Maglio, Ornella; Nastri, Flavia; Lombardi, Angela;
Mazzeo, Marco; Morelli, Giancarlo; Paolillo, Livio; Pedone, Carlo; Pavone,
Vincenzo. Chemistry--A European Journal (1997), 3(3), 350-362.
59
Abstract: FeIII mimochrome I is the prototype of a new class of
hemoprotein models characterized by a covalent helix-heme-helix
sandwich. It contains deuterohemin bound through two propionyl groups to
two identical N- and C-terminal protected α-helical nonapeptides, each of
which bears a His residue (a potential axial ligand of the iron ion) in the
central position. To understand better the three-dimensional structure of
FeIII mimochrome I and its correlation with spectral properties, we have
characterized the fully diamagnetic parent compd. CoIII mimochrome I by
UV/visible, CD, and NMR spectroscopy, coupled with conformational
energy calcns. CoIII mimochrome I is a highly water-sol. compd. present in
soln. as two isomers, which slowly interconvert only at very low pH values.
These isomers were isolated and sep. characterized. Their UV/visible
spectral properties are very similar, while their CD spectral properties differ
markedly in both the far UV and Soret regions. The isomers were identified
by 1H NMR spectroscopy as diastereomers of the ∆ and Λ type. This is the
first example of an accurate three-dimensional structure detn. in soln. of a
hemoprotein mimetic that allows a straightforward correlation between
structure and spectral properties.
28.
Hemoprotein models based on a covalent helix-heme-helix sandwich: 1.
Design, synthesis, and characterization. Nastri, Flavia; Lombardi, Angela;
Morelli, Giancarlo; Maglio, Ornella; D'Auria, Gabriella; Pedone, Carlo;
Pavone, Vincenzo. Chemistry--A European Journal (1997), 3(3), 340-349.
Abstract: In this paper we describe design, synthesis, and spectroscopic
characterization of a covalent helix-heme-helix sandwich named FeIII
mimochrome I. It contains deuterohemin bound through both propionyl
groups to two identical N- and C-terminal protected nonapeptides as αhelical scaffolds. Each peptide moiety bears a His residue in the central
position, which acts as axial ligand to the metal ion. The newly developed
synthetic strategy is based on a combination of soln. and solid-phase
methodologies. It represents a powerful method for obtaining a large variety
of analogs contg. two sym. or unsym. peptide chains covalently bound to
the deuteroporphyrin ring. UV/Visible spectroscopic characterization in
buffered 2,2,2-trifluoroethanol/water soln. proves low-spin bis(histidine)
iron(III) coordination; CD (CD) measurements show an α-helical
conformation for the peptide moieties. Thus, all the data are in agreement
with the designed hypothetical model regarding both the iron(III)
coordination and the peptide chain structural organization.
29.
A racemic bicyclic acylamidine from a tripeptide derivative. Saviano,
Michele; Lombardi, Angelina; Pavone, Vincenzo; Yamada, Takashi;
60
Yanagi, Takashi; Iwamoto, Akira; Kuwata, Shigeru. Acta Crystallographica,
Section C: Crystal Structure Communications (1996), C52(7), 1705-1708.
Abstract:
2,2,8-Triisopropyl-4,5,7,8-tetrahydroimidazo[1,2-a]pyrazine-3,6dione is monoclinic, space group P2/n, with a 12.533(2), b 7.6536(9), c
16.804(2) .ANG., and β 101.03(1)°; Z = 4, dc = 1.173; R = 0.045, Rw = 0.042 for
2700 reflections. At. coordinates are given. The mol. has a double bond and
two partial double bonds in the bicyclic skeleton, with some π-electron
delocalization along C'1-N3-C'2. The conformation parameters of the
diisopropyl (Dip) residue reveal that it is in an unusually high-energy
conformation. The peptide bond between the glycine and valine residues is
cis [Cα3-C'3-N1-Cα1 = -7.0(3)°]. In the crystal, the mols. are held together
in the ac plane by intermol. H bonds formed around a 2-fold axis by mols.
related by symmetry centers.
30.
Crystal and Molecular Structure of the [6-Deoxy-6-[(2-(4imidazolyl)ethyl)amino]cyclomaltoheptaose]copper(II) Ternary Complex
with L-Tryptophanate. Role of Weak Forces in the Chiral Recognition
Process Assisted by a Metallocyclodextrin. Bonomo, Raffaele P.; Di Blasio,
Benedetto; Maccarrone, Giuseppe; Pavone, Vincenzo; Pedone, Carlo;
Rizzarelli, Enrico; Saviano, Michele; Vecchio, Graziella. Inorganic Chemistry
(1996), 35(15), 4497-4504.
Abstract:
The
ternary
Cu(II)
complex
of
6-deoxy-6-[(2-(4imidazolyl)ethyl)amino]cyclomaltoheptaose (CDhm) and L-tryptophanate
(L-TrpO-) was prepd. characterized by ESR and x-ray diffraction. The solid
state structure of [Cu(CDhm)(L-TrpO)]+ shows that the arom. side chain
of TrpO- is outside the cavity and that the two amino N atoms, one from
the histamine mol. and one from the amino acidate, are in a cis disposition.
The two amino nitrogens, the imidazole N, and the carboxylate O atoms
form the base of a square pyramid, which surrounds the Cu(II) ion, a H2O
mol. occupying an apical position. At. distances suggest for this complex
that π-π and d-π interactions could occur in the solid state. The
[Cu(CDhm)(L-TrpO)]+ has a self-assembled structure in which a CDhm
mol. behaves as host and as guest. The imidazole and the indole ring are
directed into the cavity of an adjacent CDhm mol. from the wider
cyclodextrin rim, thus forming a polymeric column structure. ESR spectra
were run on the Cu(II) ternary complexes with L- or D-tryptophanate and
L- or D-alaninate in frozen aq. soln. and on the former pair of enantiomers
in the solid state, as well. While in the case of the ternary complex with Lor D-alaninate no differences are obsd. in their frozen soln. spectra, in the
case of complexes with TrpO- subtle differences are found. These
differences, which disappear when excess MeOH was used, are ascribed to
61
the presence of weak forces, such as hydrophobic or d-π interactions.
31.
Discovering protein secondary structures: classification and description of
isolated α-turns. Pavone, Vincenzo; Gaeta, Girolamo; Lombardi, Angela;
Nastri, Flavia; Maglio, Ornella; Isernia, Carla; Saviano, Michele.
Biopolymers (1996), 38(6), 705-721.
Abstract: Irregular protein secondary structures are believed to be important
structural domains involved in mol. recognition processes between proteins,
in interactions between peptide substrates and receptors, and in protein
folding. In these respects, tight turns are being studied in detail. They also
represent template structures for the design of new mols. such as drugs,
pesticides, or antigens. Isolated α-turns, not participating in α-helical
structures, have received little attention due to the overwhelming presence
of other types of tight turns in peptide and protein structures. The growing
no. of protein x-ray structures allowed the authors to undertake a
systematic search into the Protein Data Bank of this uncharacterized
protein secondary structure. A classification of isolated α-turns into
different types, based on conformational similarity, is reported here. A
preliminary anal. on the occurrence of some particular amino acids in
certain positions of the turned structure is also presented.
32.
Solvent-mediated conformational transition in β -alanine-containing cyclic
peptides. VIII. Lombardi, Angela; Saviano, Michele; Nastri, Flavia; Maglio,
Ornella; Mazzeo, Marco; Isernia, Carla; Paolillo, Livio; Pavone, Vincenzo.
Biopolymers (1996), 38(6), 693-703.
Abstract: We describe the soln. NMR structural anal. and restrained mol.
dynamics simulation of the cyclic pentapeptide cyclo-(Pro-Phe-Phe-β-Alaβ-Ala). The conformational anal., carried out in CD3CN and DMSO solns.
by NMR spectroscopy, was based on interproton distances derived from
rotating frame nuclear Overhauser effect spectroscopy and homonuclear
coupling consts. A restrained mol. dynamics simulation in vacuo was also
performed to build refined mol. models. The mol. is present in both solvent
systems as two slowly interconverting conformers, characterized by a cistrans isomerism around the β-Ala5-Pro1 peptide bond. In CD3CN soln., the
conformer with a cis peptide bond is quite similar to that obsd. in the solid
state, while the conformer contg. all trans peptide bonds is characterized by
an intramol. hydrogen bond stabilizing a C10- and a C13-ring structure. In
DMSO soln., the trans isomer is partly similar to that obsd. in CD3CN
soln. while the cis isomer is different from that obsd. in the solid state. The
effect of the solvent in stabilizing different conformations was also
investigated in DMSO-CD3CN solvent mixts.
62
33.
Unusual conformational preferences of β-alanine containing cyclic peptides.
VII. Lombardi, Angela; Saviano, Michele; Nastri, Flavia; Maglio, Ornella;
Mazzeo, Marco; Pedone, Carlo; Isernia, Carla; Pavone, Vincenzo.
Biopolymers (1996), 38(6), 683-691.
Abstract: The synthesis, purifn., and single crystal X-ray anal. of cyclic
pentapeptide cyclo(Pro-Phe-Phe-β-Ala-β-Ala) were carried out. In the solid
state this compd. adopts an unusual conformation characterized by a cis βAla5-pro1 peptide bond and by an intramol. hydrogen bond stabilizing a C11and a C12-ring structure. The C11 structure contains the Phe3 and the β-Ala4
at the corner position of the turn; it is the first observation of a type II βturn enlargement due to the insertion of an extra methylene group of the βalanine residue. The rest of the mol. participates in a newly characterized
C12-ring structure, which incorporates a β-Ala residue at position i of the
turn.
34.
A modified cyclodextrin with a fully encapsulated dansyl group: selfinclusion in the solid state and in solution. Corradini, Roberto; Dossena,
Arnaldo; Marchelli, Rosangela; Panagia, Anna; Sartor, Giorgio; Saviano,
Michele; Lombardi, Angela; Pavone, Vincenzo. Chemistry--A European
Journal (1996), 2(4), 373-81.
Abstract: A monofunctionalized β-cyclodextrin contg. a dansyl moiety, 6deoxy-6-N-[N'-(5-dimethylamino-1-naphthalenesulfonyl)diaminoethane]β-cyclodextrin (I), was synthesized and its crystal structure was detd. It
was shown that the dansyl group is fully encapsulated within the
cyclodextrin cavity, with the dimethylamino and sulfonyl groups emerging
from opposite sides. The conformation of the diaminoethane linker was
found to be detd. by the inclusion of the dansyl group and by a hydrogen
bond between the sulfonamide NH and one of the O(6)-H groups on the
cyclodextrin rim. Fluorescence spectra showed that the inclusion of the
dansyl group in the cyclodextrin cavity considerably increases the quantum
yield; time-resolved fluorescence expts. showed the presence of a longlifetime component (16.1 ns), which was attributed to the included
fluorophore. The ability of I to act as a fluorescence sensor was evaluated by
the addn. of several guests of different shape: fluorescence intensity was
lowered, esp. upon addn. of adamantane-carboxylic acid. Copper(II) was
shown to enhance the difference in the fluorescence of I in the presence of
guests by addnl. static quenching.
35.
Rational Design of True Hirudin Mimetics: Synthesis and Characterization
63
of Multisite-Directed α -Thrombin Inhibitors. Lombardi, Angela; Nastri,
Flavia; Della Morte, Rossella; Rossi, Armando; De Rosa, Alfredo; Staiano,
Norma; Pedone, Carlo; Pavone, Vincenzo. Journal of Medicinal Chemistry
(1996), 39(10), 2008-17.
Abstract: We describe here the design, synthesis, and activity of a novel
class of α-thrombin inhibitors named hirunorms. They were rationally
designed to interact through their N-terminal end with the α-thrombin
active site in a nonsubstrate mode and to specifically bind the fibrinogen
recognition exosite. An appropriate spacer that is able to properly orient the
N-terminal end in the active site was also selected. This spacer allowed the
size of the inhibitors to be reduced to about one-third of the amino acid
residues in the hirudin sequence. Hirunorms specifically inhibit the
amidolytic action of human α-thrombin toward a small chromogenic
substrate. The most active compds. of the series, hirunorms IV and V,
inhibit α-thrombin catalyzed hydrolysis of Tos-Gly-Pro-Arg-p-nitroanilide
with Ki = 0.09 and Ki = 0.21 nM, resp. Comparison of the anticoagulant
properties of hirunorms, natural hirudin from the European leech Hirudo
medicinalis, and the synthetic analog hirulog-1 revealed that hirunorm IV is
about 10-fold and 3-fold more active, on a molar base, than hirudin and
hirulog-1 in increasing the aPTT, PT, and TT of normal human plasma.
The peculiar structure of hirunorms makes them stable to the amidolytic
action of thrombin without the introduction of any peptide bond
modification. These mols. display long-lasting activity in human plasma,
due to the presence of several unnatural amino acids in susceptible
positions. Hirunorms are potential candidates for injectable anticoagulants,
due to their potency, specificity of action, long-lasting activity, and safety
profiles.
36.
Bicyclic peptides as type I/type II beta-turn scaffolds. Lombardi A; D'Auria
G; Saviano M; Maglio O; Nastri F; Quartara L; Pedone C; Pavone V
Biopolymers (1996), 40(5), 505-18.
Abstract: We recently reported the rational design, synthetics, and structural
characterization of the most potent and selective peptide-based neurokinin
A antagonist thus far described: cyclo(Met1-Asp2-Trp3-Phe4-Dap5Leu6)cyclo(2 beta-5 beta). Its bicyclic structure is characterized by a type I
and a type II two beta-turn around Trp3-Phe4 and Leu6-Met1, respectively.
In order to understand whether the two different beta-turned structures are
determined by the bicyclic structure or by the amino acid type at the corner
positions, we have synthesized the pseudo-symmetrical analogue
cyclo(Phe1-Asp2-Trp3-Phe4-Dap5-Trp6)cyclo(2β-5β).
The
structural
characterization in the crystal state and in solution, here reported, gives an
64
experimental evidence that the backbone of the bicyclic structure is a rigid
scaffold that can be used to build both a type I and type II beta-turn
independently from the amino acid composition.
37.
Conformational behavior of a cyclolinopeptide A analog: two-dimensional
NMR study of cyclo(Pro1-Pro-Phe-Phe-Ac6c-Ile-ala-Val8). Mazzeo, Marco;
Isernia, Carla; Fossi, Filomena; Saviano, Michele; Pedone, Carlo; Paolillo,
Livo; Benedetti, Ettore; Pavone, Vincenzo. Journal of Peptide Science (1995),
1(5), 330-40.
Abstract: The title cyclic octapeptide cyclo(Pro1-Pro-Phe-Phe-Ac6c-Ile-DAla-Val8) (I; Ac6c = 1-aminocyclohexane-1-carboxylic acid), contg. the
Pro1-Pro-Phe-Phe sequence, followed by a bulky helicogenic Cα,αdialkylated glycine residue Ac6c and a D-Ala residue at position 7 has been
synthesized. Peptide Iis a deletion analog of the naturally occurring cyclic
nonapeptide cyclolinopeptide A(CLA). I has been designed with the aim of
studying the role that the Ac6c and D-Ala residues play on the
conformational behavior of the whole mol. and their influence on the
conformation of the Pro1-Pro-Phe-Phe sequence when compared with
cyclolinopeptide A. I has been investigated in chloroform and acetonitrile
solns. by 2-dimensional NMR techniques. Only one set of sharp signals is
obsd. in both solvents. The evidence strongly supports the hypothesis that
only one conformational state exists in the chosen solvents. The
interpretation of the exptl. data points to the existence of a very rigid
structure stabilized by intramol. hydrogen bonds. The measured NOE
effects allow the calcn. of internuclear distances, which have been used as
restraints in mol. dynamic calcns. The proposed conformation of the mol.
shows that the Pro-Pro-Phe segment retains the conformation obsd. in
natural CLA both in soln. and in the solid state and that the Ac6c residue
indeed reinforces the ring rigidity not permitting the formation of any
appropriate cavity in which inorg. cations could be complexes.
38.
Design of metal ion binding peptides. Fattorusso, R.; Morelli, G.; Lombardi,
A.; Nastri, F.; Maglio, O.; D'Auria, G.; Pedone, C.; Pavone, V.. Biopolymers
(1995), 37(6), 401-10.
Abstract: Two cyclic and branched peptides (PLA and AZU) were
synthesized with the aim of reproducing the active site of the blue copper
proteins plastocyanin and azurin. Both peptides, designed on the basis of the
X-ray structures of Poplar plastocyanin and Alcaligenes denitrificans
azurin, contain the same coordinating residues of the parent native proteins.
The visible spectra of PLA in the presence of equimolar amt. of Cu(II)
strongly support the interaction between the peptide and copper(II) ion.
65
The CD titrn. of AZU with the Hg(II) ion indicates the formation of two
species, [AZUHg]+ and [AZUHg2]3+ having binding consts. (Keq) of 3.106
and 2.104 M-1, resp.
39.
Conformational rigidity versus flexibility in a novel peptidic neurokinin A
receptor antagonist. Pavone, Vincenzo; Lombardi, Angelina; Maggi, Carlo
Alberto; Quartara, Laura; Pedone, Carlo. Journal of Peptide Science (1995),
1(4), 236-40.
Abstract: Neurokinin A receptor antagonists have been proposed as a new
class of drugs for several applications in humans (asthma, intestinal
motility, etc.). The rational design, synthesis, structural characterization
and biol. activity evaluation of a new potent, highly selective, long-lasting,
peptide based receptor antagonist are reported. The structure-activity
relation indicates that the conformational rigidity dets. potency, specificity
and esp. the long life of the mol. in the living body. MEN 10627 is the
prototype of a new class of cyclic, peptide-based, neurokinin A receptor
antagonists and it is a suitable candidate for clin. testing in humans.
40.
Design and structure of a novel Neurokinin A receptor antagonist cyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6-)cyclo(2β-5β).
Pavone,
Vincenzo;
Lombardi, Angelina; Nastri, Flavia; Saviano, Michele; Maglio, Ornella;
D'Auria, Gabriella; Quartara, Laura; Maggi, Carlo Alberto; Pedone, Carlo.
Journal of the Chemical Society, Perkin Transactions 2: Physical Organic
Chemistry (1995), (5), 987-93.
Abstract: The rational design, synthesis and solid state and soln. structural
characterization of title compd. I (Dap = L-2,3-diaminopropanoic acid)
(MEN 10627), the most potent and selective peptide-based neurokinin A
(NKA) antagonist thus far described is reported. The bioactive
conformation of the known NKA antagonist cyclo(Met1-Gln2-Trp3-Phe4Gly5-Leu6) was predicted by comparison with the known structures of
other cyclohexapeptides. On this basis the authors designed the highly
constrained I. I was synthesized efficiently, using a combined soln. and
solid phase strategy. I was fully characterized in the solid state by x-ray
crystallog. and I is shown to adopt an almost identical conformation in
acetonitrile soln. by NMR spectroscopy. This structure fully confirms the
author's hypothetical model. The structure and conformational rigidity of I
in soln. explain the high potency and selectivity and the resistance to
proteolytic degrdn. Therefore the structural requirements for NKA
antagonistic activity are clarified.
66
Me t-A sp-Trp-Phe-D a p-L eu
I
41.
MEN 10,627, a novel polycyclic peptide antagonist of tachykinin NK2
receptors. Maggi, Carlo Alberto; Astolfi, Mara; Giuliani, Sandro; Goso,
Cristina; Manzini, Stefano; Meini, Stefania; Patacchini, Riccardo; Pavone,
Vincenzo; Pedone, Carlo; et al. Journal of Pharmacology and Experimental
Therapeutics (1994), 271(3), 1489-500.
Abstract: We describe the in vitro and in vivo pharmacol. properties of
MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2β-5β), the first
example of a polycyclic peptide tachykinin NK2 receptor antagonist. MEN
10,627 is endowed with high affinity for NK2 receptor expressed in various
species with pKB values ranging between 10.1 (hamster trachea) and 8.1
(rabbit pulmonary artery). The antagonism is of competitive type in both
functional and radioligand binding assays. A 100- to 10,000-fold selectivity
was found vs. NK1 or NK3 receptors expressed in various species. As an
NK2 receptor antagonist, MEN 10,627 is 10- to 100-fold more potent than the
monocyclic peptide antagonist L 659,877 or cyclo(Met-Gln-Trp-Phe-GlyLeu). At the hamster NK2 receptor, MEN 10,627 is about 30-fold more
potent than the nonpeptide NK2 receptor antagonist SR 48,968 [(S)-Nmethyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4dichlorophenyl)butyl)benzamide], whereas the converse is true for the
rabbit NK2 receptor. Furthermore, MEN 10,627 is, up to micromolar
concns., devoid of antagonist properties toward a wide range of transmitters
of both peptide and nonpeptide nature. In urethane-anesthetized rats in
vivo, MEN 10,627 (10-100 nmol/kg i.v.) produced long-lasting inhibition of
contraction of the urinary bladder and duodenum produced by i.v.
administration of the NK2 receptor agonist [βAla8]NKA(4-10), without
affecting the responses produced by i.v. administration of the NK1 receptor
agonist [Sar9]SP sulfone or acetylcholine. In anesthetized rats, both MEN
10,627 and SR 48,968 blocked urinary bladder contraction induced by the
NK2 receptor agonist after i.v., intranasal or intraduodenal administration.
Equieffective doses of MEN 10,627 producing about 50% inhibition of the
response to [βAla8]NKA(4-10) in the rat urinary bladder in vivo, were 0.01,
0.03 and 3 µmol/kg after i.v., intranasal and intraduodenal administration,
resp. The corresponding doses of SR 48,968 were 0.03, 0.1 and 1 µmol/kg,
after i.v., intranasal and intraduodenal administration, resp. In conclusion,
MEN 10,627 is a potent and selective NK2 receptor antagonist, endowed
with high potency and long duration of action in vivo, which is not
restricted to parenteral administration. Therefore, MEN 10,627 overcomes
67
some of the most common drawbacks for the use of peptides as drugs, and
appears as a serious candidate for testing the potential usefulness of NK2
receptor antagonists in humans.
42.
Mixed conformation in Cα,α-disubstituted tripeptides: x-ray crystal
structures of Z-Aib-Dph-Gly-OMe and Bz-Dph-Dph-Gly-OMe. Pavone,
V.; Lombardi, A.; Saviano, M.; DiBlasio, B.; Nastri, F.; Fattorusso, R.;
Zaccaro, L.; Maglio, O.; Yamada, T.; et al. Biopolymers (1994), 34(12), 1595604.
Abstract: The synthesis and solid-state mol. structure of fully protected
tripeptides contg. Cα,α-diphenylglycine (Dph), namely Z-Aib-Dph-GlyOMe (Z = PhCH2O2C, Aib = Cα,α-dimethylglycine) and Bz-Dph-DphGly-OMe are reported. The mol. conformation around the Dph residue,
contg. two bulky substituents, is fully extended, while the Aib residue,
contg. two smaller groups on the Cα atom, adopts the typical 310/α-helical
conformation. Gly residues, without substituents on the Cα atom, show
different conformational preferences. Each residue seems to behave, from a
conformational point of view, independently from the presence of the other
residues, and thus mixed local conformations (folded and extended) are
present in the crystals. A nonconventional peptide synthesis, using the Ugi
reaction, is also reported.
43.
β-Alanine containing cyclic peptides with turned structure: the "pseudo
type II β -turn." VI. Pavone, Vincenzo; Lombardi, Angelina; Saviano,
Michele; Nastri, Flavia; Fattorusso, Roberto; Maglio, Ornella; Isernia,
Carla; Paolillo, Livio; Pedone, Carlo. Biopolymers (1994), 34(11), 1517-26.
Abstract: We describe the synthesis, purifn., single crystal x-ray anal., and
NMR soln. characterization, combined with restrained mol. dynamic
simulations, of the cyclic hexapeptide cyclo(L-Pro-L-Phe-β-Ala)2. The
peptide was synthesized by classical soln. methods and the cyclization of
the free hexapeptide was accomplished in good yields in dild. methylene
chloride soln. using DCC. The compd. crystallizes in the monoclinic space
group P21 from methanol-dichloromethane soln. The two identical halves of
the mol. adopt in the solid state two different conformations. One β-Ala-LPro peptide bond is trans, while the second is cis. The mol. is present in
dimethylsulfoxide d6 solns. as a mixt. of conformational families. One of
these corresponds to a C2 sym. mol. with both β-Ala-Pro cis peptide bonds,
while the second major conformation is very similar to that obsd. in the
solid state. All Pro-Phe segments, both in the solid state and the sym. and
unsym. soln. conformations, display φ,ψ angles close to that of position i + 1
68
and i + 2 of type II β-turns. In addn., the segments preceded by a trans βAla-pro peptide bond are characterized by a typical i ← i + 3 hydrogen bond,
which is absent in the conformer contg. a cis β-Ala-Pro peptide bond. The
latter conformation corresponds to a new structural domain we define as the
"pseudo type II β-turn.".
44.
β-Alanine containing cyclic peptides with predetermined turned structure.
V. Pavone, Vincenzo; Lombardi, Angelina; Saviano, Michele; Di Blasio,
Benedetto; Nastri, Flavia; Fattorusso, Roberto; Maglio, Ornella; Isernia,
Carla. Biopolymers (1994), 34(11), 1505-15.
Abstract: We describe the synthesis, purifn., single crystal x-ray anal., and
soln. structural characterization by NMR spectroscopy, combined with
restrained mol. dynamic simulations, of the cyclic hexapeptide cyclo(ProPhe-β-Ala-Phe-Phe-β-Ala). The peptide was synthesized by classical soln.
methods and the cyclization of the free hexapeptide was accomplished in
good yields in dild. methylenechloride soln. using DCC. The compd.
crystallizes in the monoclinic space group P21 from methanol/ethyl acetate.
The mol. adopts in the solid state a conformation characterized by cis βAla6-Pro1 peptide bond. The α-amino acid residues are at the corner
positions of turned structures. The Pro1-Phe2 segment is incorporated in a
pseudo type I β-turn, while Phe4-Phe5 is in a typical type I β-turn.
Assignment of all 1H and 13C resonances was achieved by homo- and
heteronuclear two-dimensional techniques in DMSO solns. The
conformational anal. was based on interproton distances derived from
rotating frame nuclear Overhauser effect spectroscopy spectra and
homonuclear coupling consts. Restrained mol. dynamic simulation in vacuo
was also performed to built refined mol. models. The mol. is present in
DMSO soln. as two slowly interconverting conformers, characterized by a
cis-trans isomerism around the β-Ala6-Pro1 peptide bond. This work
confirms our expectations on the low propensity of β-alanyl residues to be
positioned at the corners of turned structure.
45.
Influence of Lipophilicity on the Biological Activity of Cyclic
Pseudopeptide NK-2 Receptor Antagonists. Quartara, Laura; Fabbri,
Gaetano; Ricci, Renzo; Patacchini, Riccardo; Pestellini, Vittorio; Maggi,
Carlo Alberto; Pavone, Vincenzo; Giachetti, Antonio; Arcamone, Federico.
Journal of Medicinal Chemistry (1994), 37(21), 3630-8.
Abstract: A series of cyclic pseudopeptides cyclo(Leuψ[CH2NH]Xaa-GlnTrp-Phe-β-Ala) (I; Xaa = α-amino acid residue), was prepd. to establish the
role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity.
69
Syntheses have been carried out in solid phase with either 9fluorenylmethoxycarbonyl (Fmoc) or tert-butoxycarbonyl (Boc) strategy.
The antagonist potency on NK-2 receptors in the hamster isolated trachea
(HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases
with Xaa lipophilicity; I [Xaa = β-cyclohexylalanine, Asp(NHCH2Ph)]
were the two most active antagonists (pA2 = 9.06 and 9.26 on HT, resp.). A
significant linear correlation was found between pA2 values detd. in HT
and RPA bioassays and capacity factors measured in reversed phase HPLC.
The comparison between the biol. activities of cyclic hexapeptides contg. or
not contg. the aminomethylene moiety proved the crucial role of the
pseudopeptide bond for detg. high antagonist potency at the NK-2 receptor.
46.
Conformational studies on peptides as enzyme inhibitors: chymotrypsin
inhibitors using Bowman-Birk type as models. Pavone, Vincenzo; isernia,
Carla; Saviano, Michele; Falcigno, Lucia; Lombardi, Angelina; Paolillo,
Livio; Pedone, Carlo; Buoen, Solfrid; Naess, Hilde Merete; et al. Journal of
the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (19721999) (1994), (5), 1047-53.
Abstract: A complete structural characterization in soln., by NMR
spectroscopy, and in vacuo, by mol. dynamic simulations, of two synthetic
peptide fragments from SBB (soybean Bowman-Birk inhibitor) is reported.
Peptide 197 I, corresponding to the SBBI(41-49) chymotrypsin recognition
site, has free N- and C-terminal groups, while peptide 212 II, corresponding
to the Leu-16-SBBI(14-22) has uncharged and fully protected terminal ends.
Peptide 212 shows significant antichymotryptic activity while peptide 197 is
inactive. Neither of the two peptides shows anti-tryptic activity. The
structural information obtained in the present paper suggests a quant.
structure-activity relationship which may help both in understanding the
mechanism of action of protease inhibitors, and in providing new directions
for the rational design of more specific and potent inhibitors.
H-C ys-Ala-Leu-Ser-Tyr-Pro-Ala-Gln-C
Ac-C ys-Thr-Leu-Ser-Asn-Pro-Pro-Gln-C
47.
ys-OH
ys-NH 2
I
II
Conformational versatility of the Nα-acylated tripeptide amide tail of
oxytocin. Synthesis and crystallographic characterization of three C2α backbone modified, conformationally restricted analogs. Fabiano, N.; Valle,
G.; Crisma, M.; Toniolo, C.; Saviano, M.; Lombardi, A.; Isernia, C.;
Pavone, V.; Di Blasio, B.; et al. International Journal of Peptide & Protein
Research (1993), 42(5), 459-65.
70
Abstract: The synthesis, phys. and anal. characterization, and crystal-state
structural anal. by x-ray diffraction of R-Pro-X-Gly-NH2 [I; R = Me3CO2C
(Boc), X = 1-aminocyclopropane-1carboxylic acid (Ac3c); R = PhCH2O2C
(Z),
X
=
1-aminocyclopentane-1-carboxylic
acid
(Ac5c),
1aminocyclohexane-1-carboxylic acid (Ac6c)], analogs of the Nα-acylated
tripeptide amide tail of oxytocin, each contg. a cyclic Cα,α-disubstituted
glycine at position 2, have been performed. While I (R = Boc, X = Ac3c) is
folded in a type-II β-turn conformation at the Pro-Ac3c sequence, I (R = Z,
X = Ac5c, Ac6c) form two consecutive (type-II, type-I') β-turns. I (R = Z, X
= Ac5c, Ac6c) are the first examples of such a highly folded structural
combination in a position-2 analog of the Nα-acylated Pro-Leu-Gly-NH2
sequence.
48.
β-Alanine containing peptides: γ -turns in cyclotetrapeptides. Di Blasio, B.;
Lombardi, A.; D'Auria, G.; Saviano, M.; Isernia, C.; Maglio, O.; Paolillo, L.;
Pedone, C.; Pavone, V.. Biopolymers (1993), 33(4), 621-31.
Abstract: The synthesis, purifn., single-crystal x-ray anal., soln.
conformational characterization, and conformational energy calcns. of the
cyclic tetrapeptide cyclo(β-Ala-L-Pro-β-Ala-L-Val) are described.. The
the free tetrapeptide was accomplished in good yields in dild. methylene
chloride soln. using DCC. The compd. crystallizes in the monoclinic space
group P21 from ethanol with two independent mols. in the unit cell. All
peptide bonds are trans. The NMR mol. conformation in the acetonitrile
soln. as well as that derived from the mol. dynamic simulation in vacuo is
quite different from those obsd. in the solid state and is very similar to that
previously obsd. for the parent compd. cyclo(β-Ala-L-Pro-β-Ala-L-Pro).
49.
Platinum(II) complexes of amino acids and peptides. III. X-ray diffraction
study of [Cl(Ph3P)Pt(H-Aib-O)]. Lombardi, Angela; Maglio, Ornella;
Pavone, Vincenzo; Di Blasio, Benedetto; Saviano, Michele; Nastri, Flavia;
Pedone, Carlo; Benedetti, Ettore. Inorganica Chimica Acta (1993), 204(1), 8792.
Abstract: [Cl(Ph3P)Pt(L)] (I; HL = α-aminoisobutyric acid) was
synthesized and characterized in the solid state by x-ray diffraction anal. I
was characterized by x-ray crystallog. Crystal data: I.H2O; triclinic, space
group P.hivin.1, a 9.020(1), b 10.011(2), c 13.748(1) .ANG., α 91.74(1), β
90.29(1), γ 111.26(1)°, Z = 2, R = 0.038, Rw = 0.042. The Pt(II) displays the
square planar coordination with L- acting as a bidentate ligand. The N atom
71
of L- is trans to the P atom of the PPh3, and the O atom of the carboxylate
is trans to the Cl atom. The obsd. distortions in the bond angles around the
Pt(II) atom and the conformation assumed by PPh3 and L- are explained
from the need to release the intramol. nonbonded interactions between
atoms of the various ligands. Three intermol. H bonds, involving as donors
the co-crystd. H2O mol. and the 2 H atoms of the N-H groups and as
acceptors the Cl, the O of the H2O mol., and 1 of the O atoms of the
carboxylic acid group, together with van der Waals interactions between
hydrophobic groups held the mols. in the crystal state.
50.
Non coded Cα,α-disubstituted amino acids. X-ray diffraction analysis of a
dipeptide containing (S)-α -methylserine. Pavone, V.; Di Blasio, B.;
Lombardi, A.; Maglio, O.; Isernia, C.; Pedone, C.; Benedetti, E.; Altmann,
E.; Mutter, M. International Journal of Peptide & Protein Research (1993), 41(1),
15-20.
Abstract: The crystal and mol. structure of Boc-Val-(S)-α-MeSer-OMe (Boc
= Me3CO2C) has been detd. by x-ray diffraction techniques. Both chiral
centers have the S configuration. The dipeptide assumes in the solid state
an S shape. The urethane moiety is in the cis conformation, while the amide
bond is in the common trans conformation. The conformational angles φ1,
ψ1 of the Val and φ2, and ψ2 of the (S)-αMeSer fall in the F region of the φψ map. The iso-Pr side chain of the Val residue has the (t, g-)
conformation, while the Ser side chain has a g+ conformation. The
hydrogen bond donor groups are all involved in intermol. H-bond
interactions. Along the quaternary axis the dipeptide mols. are linked to
each other with the formation of infinite rows.
51.
Platinum(II) complexes of amino acids and peptides. II. Structural analysis
of trans-[Cl2Pt(H-Aib-OH)2] and trans-[Pt(H-Aib-O-)2]. Lombardi,
Angela; Maglio, Ornella; Benedetti, Ettore; Di Blasio, Benedetto; Saviano,
Michele; Nastri, Flavia; Pedone, Carlo; Pavone, Vincenzo. Inorganica
Chimica Acta (1992), 196(2), 241-6.
Abstract: trans-[PtCl2(H-Aib-OH)2] and trans-[Pt(H-Aib-O-)2] were
prepd. and characterized in soln. and in the solid state. Their crystal and
mol. structures were detd. by x-ray diffraction. The complexes show a
distorted planar coordination around the heavy atom. The org. moiety in
the 2 complexes shows different conformations: in trans-[Pt(H-Aib-O-)2]
the amino acid residue, acting as a bidentate, is forced to assume on unusual
conformation. But in trans-[PtCl2(H-Aib-OH)2], in which the amino acid
acts as a monodentate ligand, the α-aminoisobutyric acid assumes an
extended conformation, which in general for α-monosubstituted amino
72
acid residues coordinated to the Pt should be the preferred conformation. In
both crystal structures H bonds are formed between the donor and acceptor
groups with further stabilization deriving from van der Waals interactions
between hydrophobic moieties.
52.
Conformation of diastereomeric peptide sequences: structural analysis of ZD-Val-Ac6c-Gly-L-Phe-OMe. Di Blasio, B.; Lombardi, A.; Nastri, F.;
Saviano, M.; Pedone, C.; Yamada, T.; Nakao, M.; Kuwata, S.; Pavone, V..
Biopolymers (1992), 32(9), 1155-61.
Abstract: A systematic structural anal. of fully protected tetrapeptides contg.
at the N- and C-terminus either homo- or heterochiral amino acids, spaced
by an achiral dipeptide segment was undertaken. The interest for this class
of peptides derives from the observation that, on reverse-phase HPLC, the
homo- and heterochiral sequences have a markedly different retention
times. Therefore, following preliminary studies in soln., the detailed x-ray
anal. of the tetrapeptide Z-D-Val-Ac6c-Gly-L-Phe-OMe (Z = PhCH2O2C,
Ac6c = 1-aminocyclohexane-1-carboxylic acid) are reported to understand
the structural features governing the overall hydrophobicity of linear fully
protected tetrapeptides.
53.
Conformation for a β-cyclodextrin monosubstituted with a cyclic dipeptide.
Di Blasio, Benedetto; Pavone, Vincenzo; Nastri, Flavia; Isernia, Carla;
Saviano, Michele; Pedone, Carlo; Cucinotta, Vincenzo; Impellizzeri,
Giuseppe; Rizzarelli, Enrico; Vecchio, Graziella. Proceedings of the National
Academy of Sciences of the United States of America (1992), 89(15), 7218-21.
Abstract: The structural characterization of 6-deoxy-6-cyclo(L-histidyl-Lleucyl)-β-cyclodextrin is reported. This work provides an x-ray example of
a covalently bound group that folds in such a way that the terminal apolar
side chain is retained in the hydrophobic interior of the cone-shaped
cyclodextrin cavity. The mol. structure consists of two independent mols.
with the formula C54H86N4O36⋅7.25H2O. Each mol. assumes a "sleeping
swan"-like overall shape with the hydrophobic leucine side chain inserted
inside the cavity of the macrocycle. The two independent units give rise to
a head-to-tail dimer linked by hydrogen bonds occurring between primary
and secondary hydroxyl groups of the two monomers. The packing of the
dimers produces cavities contg. water mols. There are infinite hydrophilic
channels running in the crystal, which is similar to what is found in the
structures of cyclic peptides.
54.
Linear oligopeptides. CCLXV. Synthesis and solution conformational
analysis of β -bend ribbon forming peptides. Crisma, Marco; Anzolin,
73
Michele; Bonora, Gian Maria; Toniolo, Claudio; Benedetti, Ettore; Di
Blasio, Benedetto; Pavone, Vincenzo; Saviano, Michele; Lombardi,
Angelina; et al. Gazzetta Chimica Italiana (1992), 122(7), 239-44.
Abstract: Peptides Z-(Pro-Aib)n-OMe (Z = PhCH2O2C, Aib = αaminoisobutyric acid, n = 1-4), p-BrZ-(Pro-Aib)n-OMe (n = 1-5) and pBrBz-Aib-(Pro-Aib)n-OMe (n = 1-4) were prepd. as potential model
compds. for the β-bend ribbon spiral. A conformational anal. in chloroform
soln., performed by using IR absorption and 1H NMR, strongly supports the
view that this ordered secondary structure, first obsd. at the -Aib-L-ProAib- tripeptide level, is extensively adopted by the longest oligomers.
55.
β-Alanine and β -bends. X-ray diffraction structures of three linear
oligopeptides. Pavone, Vincenzo; Di Blasio, Benedetto; Lombardi, Angela;
Isernia, Carla; Pedone, Carlo; Benedetti, Ettore; Valle, Giovanni; Crisma,
Marco; Toniolo, Claudio; Kishore, Raghuvansh. Journal of the Chemical
Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1992),
(8), 1233-7.
Abstract: A crystal-state structural anal. of Boc-L-Ala-β-Ala-NHMe (Boc =
Me3CO2C), Boc-Aib-β-Ala-NHMe (Aib =, α-aminoisobutyric acid), and
Boc-Aib-Aib-β-Ala-NHMe has been performed by x-ray diffraction. While
the conformation adopted by Boc-L-Ala-β-Ala-NHMe and Boc-Aib-β-AlaNHMe is essentially extended, Boc-Aib-Aib-β-Ala-NHMe is folded into
two consecutive intramolecularly hydrogen-bonded structures of the i + 3 →
i type (β-bends), with Aib(1)-Aib(2) and Aib(2)-β-Ala(3), resp., as corner
residues. Owning to the presence of the β-amino acid, the latter β-bend is
characterized by an unusual C11 hydrogen-bonded ring. These results
indicate that: (i) a β-amino acid may be incorporated into a β-bend without
a major perturbation of the overall geometry of this folded conformation,
and (ii) the propensity of the β-Ala residue for β-bend formation is rather
low, unless other conformational constraints (e.g. a preceding β-bend) are
present in the linear peptide mol.
56.
Bioactive peptides: x-ray and NMR conformational study of [Aib5,6-DAla8]cyclolinopeptide A. Di Blasio, Benedetto; Rossi, Filomena; Benedetti,
Ettore; Pavone, Vincenzo; Saviano, Michele; Pedone, Carlo; Zanotti,
Giancarlo; Tancredi, Teodorico. Journal of the American Chemical Society
(1992), 114(21), 8277-83.
Abstract: The conformational anal. of [Aib5,6-D-Ala8]cyclolinopeptide A,
cyclo(Pro-Pro-Phe-Phe-Aib-Aib-Ile-D-Ala-Val),
(I;
Aib
=
α-
74
aminoisobutyric acid) in the solid state and soln., has been carried out by xray diffraction and NMR spectroscopy. The structure of the orthorhombic
form of I, obtained from aq. MeOH, shows the presence of 5 intramol. NHOC hydrogen bonds, with formation of one C17 ring structure, one α-turn
(C13), one γ-turn (C7), and two β-turns (C10, one of type III and one of type
I). The Pro1-Pro2 peptide unit is cis (ω = 9°); all other units are trans. The
conformational study in soln. by NMR indicates that, even at room temp.,
the peptide is conformationally homogeneous; the structure detd. is almost
identical to that obsd. in the solid state. The soln. study reveals, also, that
the constraints imposed by the two Aib and D-Ala residues are particularly
strong, because the NMR conformational parameters are only slightly
affected by wide temp. variations and salt addn.
57.
Molecular dynamics simulation in vacuo and in solution of [Aib5,6-D-Ala8]
cyclolinopeptide A: a conformational and comparative study. Saviano,
Michele; Rossi, Filomena; Pavone, Vincenzo; Di Blasio, Benedetto; Pedone,
Carlo. Journal of Biomolecular Structure & Dynamics (1992), 9(6), 1045-60.
Abstract: The conformation of cyclolinopeptide A analog cyclo(Pro-ProPhe-Phe-Aib-Aib-Ile-D-Ala-Val) (Aib = α-aminoisobutyric acid) was
investigated by mol. dynamics simulations in various mol. environments.
The mol. dynamics results are compared with that obtained for
cyclolinopeptide A and a detailed anal. of the different behavior for the two
compds. is reported. A complete anal. of hydrogen bonds is presented.
58.
First observation of a helical peptide containing chiral α-monosubstituted
residues without a preferred screw sense. Pavone, Vincenzo; Lombardi,
Angelina; Nastri, Flavia; Saviano, Michele; Di Blasio, Benedetto; Fraternali,
Franca; Pedone, Carlo; Yamada, Takashi. Journal of the Chemical Society,
Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1992), (6), 971-7.
Abstract: The detailed x-ray structure of the fully blocked tetrapeptide
PhCH2O2C-D-Val-(Aib)2-L-Phe-OMe (Aib = α-aminoisobutyric acid) is
reported. There is a regular alternation of right- and left-handed 310-helices
hydrogen bonded head-to-tail along this axis. Pairs of mols. with the same
handedness differ in the conformation of the side chains and of the N- and
C-terminal blocking groups. This is the first observation of a helical peptide
contg. chiral α-monosubstituted α-amino acids without a preferred screw
sense. Conformational energy computations confirmed that those helices
with different handedness have comparable stabilities. This work furthers
the understanding of structural features responsible for the
diastereoselective sepn. by reversed-phase HPLC.
75
59.
Structural characterization of the β -bend ribbon spiral: crystallographic
analysis of two long (L-Pro-Aib)n sequential peptides. Di Blasio, B.;
Pavone, V.; Saviano, M.; Lombardi, A.; Nastri, F.; Pedone, C.; Benedetti,
E.; Crisma, M.; Anzolin, M.; Toniolo, C. Journal of the American Chemical
Society (1992), 114(16), 6273-7.
Abstract: The mol. and crystal structures of title peptides p-BrBz-Aib-(LPro-Aib)n-OMe (Aib = α-aminoisobutyric acid; n = 3, 4) were detd. by xray diffraction. In both crystals two mols. in the asym. unit are found.
Either mol. in the asym. unit of each structure shows a right-handed β-bend
ribbon spiral, stabilized by the max. possible no. of intramol. N-H⋅⋅⋅O:C Hbonds. Thus, for the first time it was possible to characterize at at. resoln.
this polypeptide conformation.
60.
A helical Dpg homopeptide. Di Blasio, Benedetto; Pavone, Vincenzo;
Isernia, Carla; Pedone, Carlo; Benedetti, Ettore; Toniolo, Claudio; Hardy,
Paul M.; Lingham, Ian N. Journal of the Chemical Society, Perkin Transactions
2: Physical Organic Chemistry (1972-1999) (1992), (4), 523-6.
Abstract: The first x-ray diffraction structure anal. of a helical homopeptide
of Cα,α-dipropylglycine (Dpg) has been performed for Tfa-(Dpg)3-DBH
monohydrate (Tfa = trifluoroacetyl, DBH = N',N'-dibenzylhydrazido).
61.
Characterization at atomic resolution of peptide helical structures.
Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Toniolo, C.; Crisma,
M. Biopolymers (1992), 32(4), 453-6.
Abstract: A survey of literature for the various types of helices exptl. obsd.
in high-resoln. single crystal x-ray diffraction analyses of peptides allowed
the detn. of accurate conformational and helical parameters for the various
secondary structures such as the α-helix, the 310-helix, the fully extended
conformation (25-helix), and the β-bend ribbon spiral. For each of these
structures the characteristic ϕ,ψ conformational parameters, n, the no. of
residues per turn, h, the height per residues, and p, the pitch of the helix are
described.
62.
β-Alanine containing peptides: a novel molecular tool for the design of γ turns. Pavone, V.; Lombardi, A.; D'Auria, G.; Saviano, M.; Nastri, F.;
Paolillo, L.; Di Blasio, B.; Pedone, C. Biopolymers (1992), 32(2), 173-83.
Abstract: The synthesis, purifn., single crystal x-ray anal., and soln.
conformational characterization of the cyclic tetrapeptide cyclo(Pro-β-Ala-
76
Pro-β-Ala) is described. This peptide was synthesized by classical soln.
methods and the cyclization of the free tetrapeptide was accomplished in
good yields using DCC. The mol. conformation is stabilized by two
intramol. hydrogen bonds between the CO and NH groups of the two βalanine residues. These hydrogen bonds take part in a C7 structure in which
both proline residues occupy the 2 position of an inverse γ-turn. The two βalanine residues have a typical folded conformation (around the Cα-Cβ
bond) obsd. in other cyclic peptides contg. this residue. A detailed 1H-NMR
anal. in CD3CN soln. has been carried out. The mol. assumes a twofold
symmetry in soln. with a mol. conformation consistent with that obsd. in
the solid state.
63.
β-Alanyl-β-alanine in cyclic β-turned peptides. Di Blasio, B.; Lombardi, A.;
Yang, X.; Pedone, C.; Pavone, V.. Biopolymers (1991), 31(10), 1181-8.
Abstract: The synthesis, purifn., and single crystal x-ray anal. of the cyclic
pentapeptide cyclo(L-Pro-L-Pro-L-Phe-β-Ala-β-Ala) is described). The
the free pentapeptide was accomplished in good yields in dil. CH2Cl2 using
DCC. The Pro1-Pro2 peptide bond is cis and the mol. conformation is
stabilized by an intramol. hydrogen bond between the CO group of β-Ala5
and the NH of the Phe3. The Pro1-Pro2 segment occupies the relative
positions 2 and 3 of a type VIa β-turn, while the L-phenylalanyl-β-alanyl-βalanine segment is incorporated in a C13-like ring structure. The crystal
packing is characterized by a network of 11 intermol. hydrogen bonds
involving all the remaining CO, NH, and water mols.
64.
Crystal-state conformation of homo-oligomers of α -aminoisobutyric acid:
molecular and crystal structure of pBrBz-(Aib)6-OMe. Di Blasio,
Benedetto; Santini, Antonello; Pavone, Vincenzo; Pedone, Carlo; Benedetti,
Ettore; Moretto, Vittorio; Crisma, Marco; Toniolo, Claudio. Structural
Chemistry (1991), 2(5), 523-7.
Abstract: The title terminally blocked homohexapeptide 4BrC6H4CO(NHCMe2CO)6OMe was examd. by x-ray crystallog. The
compd. is folded into almost two turns of a 310-helix, stabilized by four
consecutive intramol. NH-OC hydrogen bonds. An asym. covalent
geometry for the α-aminoisobutyric acid residues, known to be responsible
for the onset of the 310-helix on the basis of a theor. conformational anal.,
has been exptl. verified in this structure.
65.
Linear oligopeptides. CCXXXI. Preferred conformation of homo-oligomers
77
of α-aminoisobutyric acid: molecular and crystal structure of Z-(Aib)7OMe. Pavone, Vincenzo; Di Blasio, Benedetto; Pedone, Carlo; Santini,
Antonello; Benedetti, Ettore; Formaggio, Fernando; Crisma, Marco;
Toniolo, Claudio. Gazzetta Chimica Italiana (1991), 121(1), 21-7.
Abstract: The structure of the title compd., 2-(Aib)7-OMe (Z = PhCH2O2C,
Aib = α-aminoisobutyric acid) was detd. by x-ray crystallog. The compd. is
folded into two complete turns of a regular 310-helix, stabilized by five
consecutive intramol. NH-OCH bonds of the β bend III (III') type. This
structure completes the series of the oligomers of α-aminoisobutyric acid to
the octapeptide level analyzed at at. resoln. by x-ray diffraction.
66.
Linear oligopeptides. 229. Preferred conformation of the terminally blocked
(Aib)10 homo-oligopeptide: a long, regular 310-helix. Toniolo, Claudio;
Crisma, Marco; Bonora, Gian Maria; Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Santini, Antonello.
Biopolymers (1991), 31(1), 129-38.
Abstract: The decapeptide 4-BrC6H4CO-(Aib)10-OCMe3 (I; Aib = αaminoisobutyric acid) was prepd. by the 5(4H)-oxazolone method, and its
crystal structure detd. I adopts a regular 310-helical structure stabilized by 8
NH-OC intramol. 1←4 (or C10) H bonds. This study has allowed the
characterization this important peptide secondary structure in great detail.
The crystal-state conformation agrees well with proposals made on the basis
of an IR absorption and 1H-NMR study in soln.
67.
Bicyclic peptides: solid state conformation of cyclo(Glu-Leu-Pro-Gly-LysLeu-Pro-Gly)cyclo(1γ-5ε)Gly. Di Blasio, Benedetto; Benedetti, Ettore;
Pavone, Vincenzo; Pedone, Carlo; Saviano, Michele; Zanotti, Giancarlo;
Blout, Elkan R. Biopolymers (1990), 30(5-6), 509-16.
Abstract: The solid state conformational anal. of the title ionophoric
homodetic bicyclic peptide I (BCP3) has been carried out by x-ray
diffraction. The structure characterized by all trans peptide bonds is
stabilized by three intramol. H bonds: a type II β-turn, a mixed type I-type
III β-turn, and a pseudo γ-turn, which involves the side chain CO and the
main-chain NH groups of the glutamic acid residue. The resulting globular
mol. presents a rather hydrophilic surface with most of the CO groups
available to hydration by the solvent mols., which are linked through H
bonds of the NH-O or OH-O types in a complicated H-bonding scheme.
The conformation obsd. in the solid state is rather different from the
conformation proposed in soln. for both the free and the Ca2+-complexed
mol.
78
68.
Linear oligopeptides. Part 227. X-ray crystal and molecular structures of two
α -helix-forming (Aib-L-Ala) sequential oligopeptides, pBrBz-(Aib-LAla)5-OMe and pBrBz-(Aib-L-Ala)6-OMe. Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Santini, Antonello; Bavoso,
Alfonso; Toniolo, Claudio; Crisma, Marco; Sartore, Luciana. Journal of the
Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999)
(1990), (11), 1829-37.
Abstract: A crystal-state structural anal. of the title compds. 4-BrC6H4CO(NHCMe2CO-Ala)n-OMe (n = 5,6) has been performed by x-ray
diffraction. The decapeptide and dodecapeptide mols. are both basically αhelical with five and seven 1 ← 5 intramol. H-bonds, resp. A similarity
between the two structures is also seen near the C-terminus, where
regularity of the α-helix is disrupted in favor of formation of intramol. Hbonds of the 1 ← 4 and 1 ← 6 types. A brief comparison with parameters and
interactions characteristic of the helices present in globular proteins has
been made.
69.
Stereochemical behavior of acyclic peptide-cation complexes. Grimaldi,
Maria; Rossi, Filomena; Saviano, Michele; Benedetti, Ettore; Pavone,
Vincenzo; Pedone, Carlo. Biopolymers (1990), 30(1-2), 197-204.
Abstract: The role of the β-turns in the peptide interaction with cations was
investigated for PhCH2O2C-Aib-Aib-Val-OMe (Aib = NHCMe2CO),
Boc-D-aIle-Ile-Ile-OMe (Boc = Me3CO2C), Boc-Leu-Leu-Leu-Leu-OMe,
and Boc-Phe-D-Phe-Phe-D-Phe-OMe. CD and 1H-NMR spectra reveal the
presence of multiple ion-bonding equil. The stoichiometry and binding
const. of the four peptides in the presence of Ca2+ ions in acetonitrile soln.
has been detd. Variable-temp. NMR spectra in the absence and in the
presence of a large excess of cation have shown that the complexation
process is not critically dependent on the conformation of the free peptide.
70.
Cyclic β -alanyl-β -alanine containing peptides: a new molecular tool for β turned peptides. Pavone, V.; Lombardi, A.; Yang, X.; Pedone, C.; Di Blasio,
B. Biopolymers (1990), 30(1-2), 189-96.
Abstract: The synthesis, purifn., and single-crystal x-ray anal. of the cyclic
tetrapeptide cyclo-(L-Pro-L-Phe-β-Ala-β-Ala) (I) is described. I contains
the β-alanyl-β-alanine dipeptide as putative cyclization arm to force the
remaining dipeptide-L-Pro-L-Phe- in a β-turned conformation. I was
synthesized by classical methods and cyclization of the free linear
79
tetrapeptide was accomplished in reasonable yields in dil. CH2Cl2. In the
solid state I shows an intramol. hydrogen bond between the CO group of
the β-Ala4 and the NH group of the β-Ala3 residue, stabilizing a type I βturn conformation in which Pro1 and Phe2 occupy the relative position 2
and 3 of the turn, resp.
71.
Crystal structure of two retro-inverso sweeteners. Benedetti, Ettore; Di
Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo; Fuller, William D.;
Mierke, Dale F.; Goodman, Murray. Journal of the American Chemical Society
(1990), 112(24), 8909-12.
Abstract: The structure of a crystal composed of 2 diastereomers, N-(Laspartyl)-N'-[(2,2,5,5-tetramethylcyclopentanyl)carbonyl]-(R)-1,1diaminoethane(L,R
isomer)
and
N-(L-aspartyl)-N'-[(2,2,5,5tetramethylcyclopentanyl)carbonyl]-(S)-1,1-diaminoethane (L,S isomer),
was solved. Both diastereomers are intensely sweet and are retro-inverso
stereoisomers of dipeptides. The crystal structure of these mols. was related
to the model to explain the sweetness of peptide-based ligands. The L shape
postulated on the basis of mol. mechanics and NMR spectroscopy is in full
agreement with the crystal structures.
72.
The longest, regular polypeptide 310 helix at atomic resolution. Pavone,
Vincenzo; Di Blasio, Benedetto; Santini, Antonello; Benedetti, Ettore;
Pedone, Carlo; Toniolo, Claudio; Crisma, Marco. Journal of Molecular
Biology (1990), 214(3), 633-5.
Abstract: A synthetic, terminally blocked homodecapeptide from the Cα,αdimethylated glycyl residue α-aminoisobutyric acid was analyzed by singlecrystal x-ray diffraction and the structure refined to R = 0.073. The compd.
crystallizes as a perfect 310 helix, stabilized by 8 consecutive intramol. NH...O:C hydrogen bonds. This is the first observation at at. resoln. of a
regular polypeptide 310 helix as long as 3 complete turns.
73.
Linear oligopeptides. CCXXV. Critical main-chain length for
conformational conversion from 310-helix to α-helix in polypeptides.
Pavone, Vincenzo; Benedetti, Ettore; Di Blasio, Benedetto; Pedone, Carlo;
Santini, Antonello; Bavoso, Alfonso; Toniolo, Claudio; Crisma, Marco;
Sartore, Luciana. Journal of Biomolecular Structure & Dynamics (1990), 7(6),
1321-31.
Abstract: To assess the minimal peptide length required for the stabilization
of the α-helix relative to the 310-helix in α-aminoisobutyric acid (Aib)-rich
peptides, the x-ray diffraction structures of terminally blocked sequential
80
hexa- and octapeptides with the general formula, -(Aib-L-Ala)n- (where n =
3 and 4, resp.), were solved. The hexapeptides were completely 310-helical
with 4 1←4 intramol. N-H…O:C H-bonds. On the other hand, the
octapeptides were essentially α-helical with 4 1←5 H-bonds; however, the
helix was elongated at the N-terminus, with 2 1←4 H-bonds, giving these
mols. a mixed α/310-helical character. In both compds., the right-handed
screw sense of the helix was dictated by the presence of the L-alanine
residues. This study represents the 1st exptl. proof for a 310 → α-helix
conversion in the crystal state induced by peptide backbone lengthening
only.
74.
Structure of clathridine zinc complex, a metabolite of the marine sponge
Clathrina clathrus. Ciminiello, Patrizia; Fattorusso, Ernesto; Mangoni,
Alfonso; Di Blasio, Benedetto; Pavone, Vincenzo. Tetrahedron (1990), 46(12),
4387-92.
Abstract: The solid state structure of the Zn complex of clathridine, a
genuine metabolite of the sponge Clathrina clathrus, was established by xray diffraction anal. The conformation of this complex in CDCl3 soln. was
investigated by NOE difference NMR expts.
75.
Linear oligopeptides. Part 202. Structural versatility of peptides containing
Cα,α-dialkylated glycines. An x-ray diffraction study of six 1aminocyclopropane-1-carboxylic acid rich peptides. Benedetti, E.; Di Blasio,
B.; Pavone, V.; Pedone, C.; Santini, A.; Barone, V.; Fraternali, F.; Lelj, F.;
Bavoso, A.; et al. International Journal of Biological Macromolecules (1989),
11(6), 353-60.
Abstract: The crystal structures of 6 fully blocked 1-aminocyclopropane-1carboxylic acid (Acc)-rich peptides were detd. by x-ray diffraction. The
peptides are Fmoc-(Acc)2-OMe, Ac-(Acc)2-OMe, Boc-Acc-L-Phe-OMe, 4BrC6H4CO-(Acc)3-OMe, Z-Gly-Acc-Gly-OTmb, and Boc-(Acc)4-OMe
[fmoc = 9-fluorenylmethoxycarbonyl; Boc = Me3CO2C; Z = PhCH2O2C;
Tmb = CH2C6H2(OMe)3-2,4,6]. Type-I (I') β-bends and distorted 310helices were found to be typical of the tri- and tetrapeptides, resp. In the
dipeptides too short to form β-bend conformations, other less common
structural features may be obsd. The av. geometry of the cyclopropyl
moiety of the Acc residue is asym. and the N-Cα-C' bond angle is
significantly expanded form the regular tetrahedral value. A comparison
with the structural preferences of other extensively investigated Cα,αdialkylated α-amino acids is made and the implications for the use of the
Acc residue in conformational design are examd.
81
76.
Linear oligopeptides. Part 201. Structural versatility of peptides containing
Cα,α-dialkylated glycines: conformational energy computations, IR
absorption and proton NMR analysis of 1-aminocyclopropane-1-carboxylic
acid homopeptides. Crisma, M.; Bonora, G. M.; Toniolo, C.; Barone, V.;
Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini, A.; et al.
International Journal of Biological Macromolecules (1989), 11(6), 345-52.
Abstract: Conformational energy computations on the 1-aminocyclopropane1-carboxylic acid mono-, di-, and tripeptide amides, Ac(Ac3C)nNHMe (n =
1-3), indicate that this Cα,α-dialkylated, cyclic acid residue is
conformationally restricted and that type-(I') β-bends and distorted 310helices are particularly stable conformations for the di- and tripeptide
amides, resp. The results of the theor. anal. are in agreement with those
obtained in a IR and 1H NMR investigation in CHCl3 to form soln. of
Ac3C-rich tri- and tetrapeptide esters. A comparison is also made with the
conclusions extd. from previous work on peptides rich in α-aminoisobutyric
acid, 1-aminocyclopentane-1-carboxylic acid, and 1-aminocyclohexane-1carboxylic acid.
77.
Preparation of all four diastereomers of β-phenylcysteine methyl ester
through chromatographic optical resolution of the 2,2-dimethylthiazolidine
derivatives. Nagai, Ukon; Pavone, Vincenzo. Heterocycles (1989), 28(2), 58992.
Abstract: The cis and trans isomers of thiazolidine deriv. I, prepd. from the
corresponding erythro- and threo-β-phenylcysteines, were resolved into the
enantiomers by a chiral HPLC column, from which all four chiral βphenylcysteine Me esters were obtained.
Ph
S
CO 2 Me
NH
Me Me
78.
I
Structure-toxicity relationships in the amatoxin series. Synthesis of Sdeoxy[γ (R)-hydroxy-Ile3]-amaninamide, its crystal and molecular
structure and inhibitory efficiency. Zanotti, Giancarlo; Wieland, Theodor;
Benedetti, Ettore; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo.
International Journal of Peptide & Protein Research (1989), 34(3), 222-8.
Abstract: The title compd. (I), bearing a γ-hydroxyl group in the isoleucine
side chain, was synthesized. The compd. had about the same inhibitory
82
effect on RNA polymerase II from Drosophila embryo as amanullin and the
Ile3-analog. Structure anal. by x-ray diffraction revealed that the hydroxyl
group at the carbon atom of side chain-3 has the [R]-configuration, the new
analog thus being -deoxo[δ(R)-hydroxy-[Ile3]-amaninamide. It follows that
the [S]-configuration of this chiral center is a prerequisite to maximal
toxicity. Crystallog. data demonstrating great similarity between the
peptide backbones of the new analog and those of natural amatoxins are
given.
HO
H
C
H
C
Me
Me
NH CHCONH
CH
OC
CO
NH
CH 2
CO
NH
CH 2
CHCHMeEt
HO
N
OC
S
CH 2
CHNH CO CH
CH 2 CO 2 NH
79.
N
H
NH
CO
CO
CH 2
NH
I
Bioactive peptides: solid-state and solution conformation of
cyclolinopeptide A. Di Blasio, Benedetto; Rossi, Filomena; Benedetti,
Ettore; Pavone, Vincenzo; Pedone, Carlo; Temussi, Piero Andrea; Zanotti,
Giancarlo; Tancredi, Teodorico. Journal of the American Chemical Society
(1989), 111(25), 9089-98.
Abstract: The solid-state and soln. conformational anal. of cyclolinopeptide
A, a cyclic nonapeptide isolated from linseed, is reported. The x-ray crystal
structure shows the presence of five strong transannular intramol. hydrogen
bonds with the formation of one C7, two C10 (one type I and one type III),
one C13, and one C17 ring structures. One peptide unit (linking the two
proline residues) is cis (ω = 10°); all others are trans. The conformational
study in soln. by NMR spectroscopy indicates that provided one selects the
right environment, solid-state and soln. conformations are essentially
identical, even if this cyclic system tends to give rise to a complex mixt. of
quasi-isoenergetic conformations, favored by the flexibility of the ring
enhancement by the isomerism of the proline-proline bond and by polar
solvents.
80.
Structural versatility of peptides from Cα,α dialkylated glycines: linear
Ac3c homo-oligopeptides. Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone,
C.; Santini, A.; Crisma, M.; Valle, G.; Toniolo, C. Biopolymers (1989), 28(1),
175-84.
Abstract: The crystal structures of five linear Ac3c homooligopeptides R-
83
(Ac3c)n-OMe (n = 2, R = H, 9-fluorenylmethoxycarbonyl, Ac; n = 3, R = 4BrC6H4CO; n = 4, R = Me3CO2C; Ac3c = 1-amino-1-cyclopropane
carboxylate). The results indicate the propensity of the tri- and
tetrapeptides to fold into type I β-bends and distorted 310-helices, resp., in
partial contrast to aminoisobutyrate, 1-amino-1-cyclopentane-, and cyclohexanecarboxylate homopeptides of comparable main-chain length,
were regular type III β-bends and 310-helical structures were found. When
the influence of the constraints produced by the intramol. H bonds of the
C10-type is absent, other less common structural features may be obsd. The
av. geometry of the cyclopropyl group of the Ac3c residue is asym. and the
N-Cα-C' bond angle is significantly expanded from the regular tetrahedral
value.
81.
Regularly alternating L,D-peptides. III. Hexacyclic peptides from valine or
phenylalanine. Pavone, Vincenzo; Benedetti, Ettore; Di Blasio, Benedetto;
Lombardi, Angela; Pedone, Carlo; Tomasich, Lera; Lorenzi, Gian Paolo.
Biopolymers (1989), 28(1), 215-23.
Abstract: The single-crystal x-ray analyses of 2 cyclic hexapeptides contg. an
equal no. of alternating L,D-residues as putative analogs of the metal
binding compds. enniatin and beauvericine are described. Both cyclo(L-ValD-Val)3 and cyclo(L-Phe-D-Phe)3 retain in the solid state the center of
symmetry and crystallize with 6 and 8 CF3CO2H mols., resp. The peptides
are strongly hydrogen bonded to the solvent mols. On the basis of the mol.
geometry and spatial arrangement of the peptide carbonyl groups and in
comparison with other metal binding cyclic peptides, the ability of these
mols. to interact with metal ions as 1:1 complexes was estd.
82.
Regularly alternating L,D-peptides. II. The double-stranded right-handed
antiparallel β -helix in the structure of Boc-(L-Phe-D-Phe)4-OMe. Di
Blasio, Benedetto; Benedetti, Ettore; Pavone, Vincenzo; Pedone, Carlo;
Gerber, Cristoph; Lorenzi, Gian Paolo. Biopolymers (1989), 28(1), 203-14.
Abstract: The crystal structure of Boc-(L-Phe-D-Phe)4-OMe (Boc =
Me3CO2C) has been detd. by x-ray diffraction anal. The 2 independent
octapeptide mol. form a dimer in the solid state: the 2 chains are assocd. by
interstrand hydrogen bonds (12 of the type NH-OC) with the formation of
a double-stranded antiparallel right-handed ↑↓ β5,6-helix. These double
helices can be represented as a cylinder with a hydrophilic inner core
represented by the peptide units and a hydrophobic exterior constituted by
the arom. moieties. The dimensions of the cylinder are equal to those obsd.
for Boc-(L-Val-D-Val)4-OMe. In the solid state, the dimers pack with each
other in an hexagonal fashion with the formation of layers; between the
84
layers, solvent mols. fill empty spaces.
83.
Regularly alternating L,D-peptides. I. The double-stranded left-handed
antiparallel β-helix in the structure of Boc-(L-Val-D-Val)4-OMe. Di Blasio,
Benedetto; Benedetti, Ettore; Pavone, Vincenzo; Pedone, Carlo; Spiniello,
Ottavia; Lorenzi, Gian Paolo. Biopolymers (1989), 28(1), 193-201.
Abstract: The structure of Boc-(L-Val-D-Val)4-OMe (Boc = Me3CO2C) has
been detd. by x-ray single-crystal diffraction anal. Two octapeptide chains,
related by a crystallog. binary axis, wind up around each other giving rise to
a double-stranded left-handed antiparallel ↑↓ β5,6-helix. The dimer,
stabilized by 14 interstrand NH-OC hydrogen bonds, can be regarded as a
cylinder with an hydrophilic inner core represented by the peptide units as a
hydrophobic exterior of iso-Pr groups.
84.
Linear oligopeptides. 197. Structure of the linear oligopeptide tert-butyl 1-[1(benzyloxycarbonyl)amino-1-cyclohexanecarboxamido]-1cyclohexanecarboxylate. Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone,
C.; Santini, A.; Crisma, M.; Toniolo, C. Acta Crystallographica, Section C:
Crystal Structure Communications (1989), C45(4), 634-8.
Abstract: The title compd. is triclinic, space group P.hivin.1, with a 5.971(5),
b 14.033(5), c 16.011(11) .ANG., α 103.30(39), β 92.97(65), and γ 93.25(44)°; dm =
1.16 and dc = 1.171 for Z = 2. The final R = 0.068 for 2298 reflections. At.
coordinates are given. The conformations of the urethane and peptide
CONH groups are trans. The 2 Ac6c residues show ϕ,ψ sets of torsion
angles both falling in the region of the conformational energy map where αand 310-helixes are found, but their handedness is opposite. The 2
cyclohexyl rings adopt a slightly distorted chair conformation with the NH
group in the axial position.
85.
Structural versatility of peptides from Cα,α-dialkylated glycines: an
infrared absorption and proton NMR study of homopeptides from 1aminocyclopentane-1-carboxylic acid. Crisma, M.; Bonora, G. M.; Toniolo,
C.; Benedetti, E.; Bavoso, A.; Di Blasio, B.; Pavone, V.; Pedone, C.
Abstract: The conformational preferences of terminally-blocked
homopeptides R-(Acc5)n-OCMe3 (R = PhCH2O2C, n = 1-6; R = 4BrC6H4CO, n = 4, 5; Acc5 = 1-aminocyclopentane-1-carboxylic acid residue)
in CDCl3 were assessed by IR and 1H NMR as a function of concn., temp.,
and addn. of perturbing agents. The results show that an incipient 310-helix
is first formed at the tripeptide level. A comparison is made with the
85
preferred conformation of homopeptides from the higher homolog 1aminocyclohexane-1-carboxylic acid and the open chain analog Cα,αdiethylglycine.
86.
Structural versatility of peptides from Cα,α-dialkylated glycines: a
conformational energy calculation and x-ray diffraction study of
homopeptides from 1-aminocyclopentane-1-carboxylic acid. Santini, A.;
Barone, V.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Fraternali, F.; Lelj, F.;
Pavone, V.; Pedone, C.; et al. International Journal of Biological Macromolecules
(1988), 10(5), 292-9.
Abstract: Conformational energy calcns. on the 1-aminocyclopentane-1carboxylic acid monopeptide Ac-Acc5-NHMe indicate that this Cα,αdialkylated, cyclic α-amino acid residue is conformationally restricted and
that its min. energy conformation falls in the α/310-helical region. The
results of the theor. anal. are in agreement with the crystal-state structural
tendency of R-(Acc5)n-OCMe3 (R = 4-BrC6H4CO, n = 4, 5; R =
PhCH2O2C, n = 6), which were detd. by x-ray diffraction and which also
form 310-helices. The implications for the use of Acc5 residues in designing
conformationally constrained analogs of bioactive peptides are briefly
discussed.
87.
Platinum(II) complexes of amino acids and peptides. I. Structural analysis
of trans-bis(L-alanine)dichloroplatinum. Pavone, Vincenzo; Lombardi,
Angela; Di Blasio, Benedetto; Benedetti, Ettore; Pedone, Carlo. Inorganica
Chimica Acta (1988), 153(3), 171-4.
Abstract: trans-PtCl2(L-HAlaOH)2 (HAlaOH = alanine) was prepd. by a
described literature procedure and was characterized by IR and 1H NMR
and by x-ray crystallog. Crystals are orthorhombic, space group P21221, with
a 7.460(1), b 8.544(1), c 9.754(1) .ANG., Z = 2, R = 0.038, and Rw = 0.050 for
681 reflections with I > 3.0σ(I). There is an extensive network of H bonds.
The structure is mainly characterized by double layers, held together by H
bonds, whereas the double layers interact with each other by van der Waals
interactions.
88.
Linear oligopeptides. Part CLXXII. Incorporation of a guest residue into a
host (Aib)n homooligopeptide chain: conformational analysis in
chloroform. Toniolo, Claudio; Bonora, Gian Maria; Formaggio, Fernando;
Crisma, Marco; Bavoso, Alfonso; Benedetti, Ettore; Di Blasio, Benedetto;
Pavone, Vincenzo; Pedone, Carlo. Gazzetta Chimica Italiana (1988), 118(1), 4753.
86
Abstract: IR absorption spectra of R-(Aib)n-L-Leu-(Aib)2-OMe [I; R =
PhCH2O2C (Z), Aib = α-aminoisobutyric acid, n = 0-5] in CDCl3 have
been compared with those of the ref. homopeptide series Z-(Aaib)m-OMe
(m = 3-8) in the amide-A and amide-I regions. In the former series, total
development of the 310-helical structure seems to require, at least, the full
length of the highest oligomer (8 residues), but IR spectra of a similar band
shape with significant magnitude appear as early as n = 1, which is equiv. to
two consecutive type-III β-bends. The detn. of this type of ordered
conformation has been confirmed by 1H NMR. The incorporation of a
leucine residue, albeit helicogenic, into a host (Aib)m chain tends to
decrease the stability of the 310-helices. A comparison of I (n = 5, R = Z, Ac,
4-BrC6H4CO) indicates closely similar conformational preferences.
89.
On β -hairpin classification. Pavone, Vincenzo. International Journal of
Biological Macromolecules (1988), 10(4), 238-40.
Abstract: In the present report, some ambiguities in naming and grouping
the various β-hairpin conformational types of peptides and globular proteins
are discussed. A new criterion to distinguish the residues in the loop from
those in the β-ladder, based on different H-bond schemes, is presented. A
more rational way of naming the residues in a β-hairpin, in terms of loop
residues, allows an unambiguous assignment of different β-hairpins into 4
distinct classes, and a simple relationship existing between the members of
the same class is reported. An alternative approach to identify the various βhairpin types, in terms of ring structure Cm (where m is the no. of atoms in
the ring structure) of the loop part, also fulfills the requirement of a
complete description, an unambiguous assignment, and grouping into 4
distinct classes.
90.
Structural versatility of peptides from Cα,α-dialkylated glycines. II. An IR
absorption and proton NMR study of homooligopeptides from Cα,αdiethylglycine. Toniolo, C.; Bonora, G. M.; Bavoso, A.; Benedetti, E.; Di
Blasio, B.; Pavone, V.; Pedone, C.; Barone, V.; Lelj, F.; et al. Biopolymers
(1988), 27(3), 373-9.
Abstract: The conformational preferences of the N-trifluoroacetylated
diethylglycine homopeptides F3CCO(NHCEt2CO)nOR (n = 1, R = H; n =
2-5, R = CMe3) in chloroform were detd. by IR and 1H NMR. Intramol. H
bonding was found to be the dominant factor for all NH groups. The likely
absence of a conformational transition upon increasing main-chain length,
and the remarkable stability to diln., heating, and addn. of perturbing
agents, are addnl. relevant findings of this study. These results are in
87
agreement with those of the fully extended, C5-conformation-forming
homopeptides from the higher homolog Cα,α-dipropylglycine, but contrast
dramatically to those of the homopeptides from the lower homol. Cα,αdimethylglycine, which have been shown to adopt the 310-helical structure.
Ethylglycine homopeptide conformation IR NMR.
91.
Structural versatility of peptides from Cα,α-dialkylated glycines. I. A
conformational energy computation and x-ray diffraction study of
homopeptides from Cα,α-diethylgylcine. Benedetti, E.; Barone, V.; Bavoso,
A.; Di Blasio, B.; Lelj, F.; Pavone, V.; Pedone, C.; Bonora, G. M.; Toniolo,
C.; et al. Biopolymers (1988), 27(3), 357-71.
Abstract: Conformational energy computations on diethylglycine derivs.
Ac(NHCEt2CO)nNHEt (n = 1, 2) were performed. In both cases, the Cα,αdiethylglycine residues are conformationally restricted and the min. energy
conformation corresponds to the fully extended C5 structure when the NCα-C' bond angle is smaller than 108°, as is exptl. obsd. The results of the
theor. anal. are in agreement with the crystal-state structural propensity of
the
complete
series
of
N-trifluoroacetylated
homopeptides
CF3CO(NHCEt2CO)mOR (I; m = 1, R = H; m = 2-5, R = CMe3), as detd.
by x-ray diffraction. A crystallog. planar peptide backbone was obsd. for I
(m = 3, R = CMe3). A comparison with peptides Cα,α-dimethylglycine, CαMe,Cα-ethylglycine, and Cα,α-dipropylglycine indicates that the fully
extended conformation becomes more stable than the helical structures
when both amino acid side-chain Cβ atoms are substituted.
92.
Structural studies of cyclopeptides. Solid state and solution conformation of
cyclo(L-histidyl-D-histidyl). Benedetti, E.; Bavoso, A.; Di Blasio, B.;
Pavone, V.; Pedone, C.; Paolillo, L.; D'Alagni, M. International Journal of
Peptide & Protein Research (1988), 31(2), 220-4.
Abstract: The solid-state and soln. conformations of cycle(L-His-D-His)
were detd. by x-ray diffraction anal. and NMR spectroscopy, resp. The
cyclic dipeptide retains in the solid-state a crystallog. center of symmetry:
each mol. sitting on it presents a very flat chair conformation with
alternating pos. and neg. conformational angles, whose values are in the
range 5-6°. The imidazole groups of the side chains are planar, making an
angle of 78° with the av. plane of the 2,5-piperazinedione ring. These arom.
groups are folded back over the 2,5-piperazinedione ring and they sandwich
it from opposite sides. Packing is obtained through an H-bonding scheme
which involves the N-H donors of the peptide groups as well as the N-H
groups of the imidazole moieties. In water soln., at pHs equal to 2.55 and 8,
88
the mol. retains on the av. an element of symmetry since only one set of
signals is obsd. for the His protons in the NMR spectrum. From coupling
consts., the predominant conformation was calcd. to be all gauche in
excellent agreement with the solid-state results.
93.
Long, chiral polypeptide 310-helixes at atomic resolution. Bavoso, Alfonso;
Benedetti, Ettore; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo;
Toniolo, Claudio; Bonora, Gian Maria; Formaggio, Fernando; Crisma,
Marco. Journal of Biomolecular Structure & Dynamics (1988), 5(4), 803-17.
Abstract: The crystal-state preferred conformation of the terminally blocked
hepta- and octapeptides with the general formula -(Aib)n-L-Leu-(Aib)2(where Aib = α-aminoisobutyric acid and Leu = leucine) (n = 4 and 5, resp.),
detd. by x-ray diffraction was found to be right-handed 310-helix stabilized
by 5 and 6 consecutive intramol. NH⋅⋅⋅O:C H-bonds of the C10-III type,
resp. The octapeptide structure represents the first observation at at. resoln.
of a regular, chiral 310-helix larger than 2 complete turns. In both cases the
right-handed screw sense of the helix is dictated by the presence of the
single, internal L-residue. This study confirms the propensity of short
peptides rich in Aib, the prototype of the amino acid residues dialkylated at
the α C, to adopt a 310-helical structure and is expected to help the
understanding of the conformational preferences of the membrane-active,
channel-forming, ion-transporting peptaibol antibiotics.
94.
Structural versatility of peptides from Cα,α-dialkylated glycines. An
infrared absorption and 1H nuclear magnetic resonance study of
homopeptides from 1-aminocyclohexane-1-carboxylic acid1. Crisma, M.;
Bonora, G. M.; Toniolo, C.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Pavone,
V.; Pedone, C. Macromolecules (1988), 21(7), 2071-4.
Abstract: The preferred conformation of an N- and C-protected 1aminocyclohexane-1-carboxylic acid homopeptide series, from monomer to
pentamer, in chloroform soln. was detd. by IR and 1H NMR as a function of
concn., temp., and addn. of perturbing agents. The results are in favor of the
onset of an incipent 310 helix at the tripeptide level, as found in the crystal
state. A comparison is also made with the conformational propensities of
homopeptides of 1-aminocyclopentane-1-carboxylic acid and the Cα,αdialkylated glycyl residues with linear side chains.
95.
Structural versatility of peptides from Cα,α-dialkylated glycines. A
conformational energy computation and x-ray diffraction study of
homopeptides from 1-aminocyclohexane-1-carboxylic acid1. Pavone, V.;
Benedetti, E.; Barone, V.; Di Blasio, B.; Lelj, F.; Pedone, C.; Santini, A.;
89
Crisma, M.; Bonora, G. M.; Toniolo, C. Macromolecules (1988), 21(7), 206470.
Abstract: Conformational energy calcns. on Ac-Acc6-NHMe (Acc6 = 1aminocyclohexane-1-carboxylic acid residue) indicated that the Acc6 residue
is conformationally restricted and that its min. energy conformation falls in
the α/310 helical region, irresp. of the position (either axial or equatorial) or
the α-amino group. The results of the theor. anal. are in agreement with the
crystal-state structural tendency of PhCH2O2C-(Acc6)4-OCMe3 and pBrC6H4CO-(Acc6)4-OCMe3. The implications for the use of Acc6
residues in designing conformationally constrained analogs of bioactive
peptides are briefly discussed.
96.
Long, chiral polypeptide 310-helixes. Crisma, M.; Formaggio, F.; Bonora, G.
M.; Toniolo, C.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Pavone, V.;
Pedone, C. Protides of the Biological Fluids (1987), 35 465-8.
Abstract: The IR absorption and 1H NMR analyses of well-characterized,
monodispersed, terminally blocked -(Aib)n-L-Leu-(Aib)2- (n = 0-5) peptides
are strongly in favor of the full development of a stable 310-helix for the
highest oligomer in CDCl3 soln. The x-ray structures of the hepta- and
octapeptides (n = 4 and 5, resp.) indicate the formation of right-handed 310helixes in the crystal state. The octapeptide structure represents the 1st
observation at at. resoln. of a regular, chiral 310-helix longer than 2 complete
turns.
97.
Conformations of bioactive peptides: cycloinopeptide a. Di Blasio, B.;
Benedetti, E.; Pavone, V.; Pedone, C.; Goodman, M. Biopolymers (1987),
26(12), 2099-101.
Abstract: The results of the structure detn. of cyclolinopeptide A in the solid
state by x-ray diffraction are briefly reported.
98.
Stereostructure and formation mechanism of a new substituted benzofuran
from phomenone. Capasso, Renato; Palumbo, Giovanni; Randazzo,
Giacomino; Bavoso, Alfonso; Di Blasio, Benedetto; Pavone, Vincenzo.
Tetrahedron (1986), 42(16), 4493-8.
Abstract: Treating phomenone (I), a known phytotoxic and mycotoxic
sesquiterpene, with H2SO4-MeOH 15 min at room temp. gave 65% of a new
substituted benzofuran II, whose structure was confirmed by spectral and xray anal.
90
OH
Me
O
O
CH 2 OH
HO
Me
99.
Me
O
CH 2
Me
I
CH 2 OMe
II
Linear oligopeptides. Part 157. A novel peptide conformation: first
unequivocal observation of the oxy-analog of a β -bend. Toniolo, Claudio;
Valle, Giovanni; Bonora, Gian Maria; Crisma, Marco; Formaggio,
Fernando; Bavoso, Alfonso; Benedetti, Ettore; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo. Biopolymers (1986), 25(12), 2237-53.
Abstract: The x-ray diffraction anal. of Z-(Aib)3-OH (I; Z = PhCH2O2C,
Aib = NHCMe2CO) showed the occurrence of an incipient 310-helix
characterized by one type-III (or type-III') β-bend followed by one oxyanalog of the same type of β-bend. This represents the first unequivocal
observation of the latter conformation, where the OH group of the CO2H
moiety present at the C-terminus of the peptide main chain plays the role of
the hydrogen-bonding donor. These results have been compared with those
of I⋅H2O and Z-(Aib)3-OMe.
100.
Isolation and structure determination of norsphaerol, a bis-nor-diterpene
from the red alga Sphaerococcus coronopifolius. Bavoso, Alfonso; Cafieri,
Francesco; De Napoli, Lorenzo; Di Blasio, Benedetto; Fattorusso, Ernesto;
Pavone, Vincenzo; Santacroce, Ciro. Gazzetta Chimica Italiana (1987), 117(2),
87-9.
Abstract: On the basis of spectroscopic evidence structure (I) is proposed for
norsphaerol, a bromo-bis-nor-diterpene isolated from the marine alga S.
coronopifolius. Final proof of the correctness of this formula and the detn.
of the relative stereochem. has been provided by x-ray crystallog. anal.
performed on a single crystal of I.
H
H
Me 2 C H
101.
Me
H
Br
I
Linear oligopeptides. Part 147. Chemical and crystallographic study of the
reaction between benzyloxycarbonyl chloride and α-aminoisobutyric acid.
Valle, Giovanni; Formaggio, Fernando; Crisma, Marco; Bonora, Gian
Maria; Toniolo, Claudio; Bavoso, Alfonso; Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo. Journal of the Chemical
91
Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1986),
(9), 1371-6.
Abstract: The reaction of PhCH2O2CCl (ZCl) with α-aminoisobutyric acid
(Aib) gave 3 cryst. products, which were characterized by x-ray diffraction.
Two of the products were the α- and β-forms of Z-Aib-OH (67 and 27%
yield, resp.), which differ in the orientation of the Ph ring relative to the
urethane moiety and in the packing modes. of the mols., including the
intramol. H-bonding arrangements. The third product was Z-Aib-Aib-OH
(1.5% yield). The crystal structure of (Z-Aib)2O was also detd.
102.
Cyclic peptide metal salt adducts. II. Crystal structure of the silver nitrate
cyclosarcosylsarcosine 2:1 adduct. Benedetti, Ettore; Bavoso, Alfonso; Di
Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo; Rossi, Filomena.
Inorganica Chimica Acta (1986), 116(1), 31-5.
Abstract: The title adduct is triclinic, space group P1, with a 5.410(4), b
7.562(4), c 8.020(6) .ANG., α 92.06(4), β 105.07(4), and γ 104.60(4)°; dm =
2.62(1) and dc = 2.625 for Z = 2. The final R = 0.058. The Ag ion directly
interacts with the carbonyl O atoms of the peptide moiety. The
independent unit is composed of a half cyclosarcosylsarcosine mol., which
sits on a crystallog. center of symmetry, per each AgNO3 unit. The crystal
is held together by strong coulombic interactions between the Ag and the
NO3 ions and by ion-dipole interactions between the Ag ion and the org.
mol. The coordination at the Ag ion cannot be described in terms of a
regular geometry; each Ag ion experiences different types of contacts with
the surrounding O atoms. Six Ag-O interactions are 2.35-2.68 .ANG.; a 7th
Ag-O interaction presents a distance of 2.90 .ANG.. This latter contact is
perhaps the cause of the severe distortion from the ideal octahedral
geometry obsd. exptl. The NO3 ion and the cyclic peptide mol. are both
nearly planar. At. coordinates are given.
103.
Cyclic peptide-metal salt adducts. I. Crystal structure of the
hexaquocopper(II) perchlorate cyclosarcosylsarcosine 1:2 adducts. Benedetti,
Ettore; Bavoso, Alfonso; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone,
Carlo. Inorganica Chimica Acta (1986), 123(3), 155-9.
Abstract: The title adduct is monoclinic, space group P21/c, with a 13.879(7),
b 14.504(7), c 13.083(8) .ANG., and β 90.98(10)°; dm = 1.65 and dc = 1.652 for
Z = 4. The final R = 0.083. At. coordinates are given. The independent unit
is composed of 6 H2O mols. octahedrally coordinated to the Cu(II) ion, 2
tetrahedral ClO4- ions and 4 independent halves of cyclosarcosylsarcosine
mols. lying on crystallog. centers of symmetry. All available H atoms of
92
H2O mols. are involved in H bonding as donors and all carbonyl O atoms
of the cyclic peptide mols. function as acceptors. Two other O atoms for
each ClO4- participate in the H bonding scheme, which leads to the absence
of the orientational disorder usually obsd. in these ions. Layers of inorg.
material and layers of org. material, roughly parallel to the ab plane, pack
alternatively with each other. Electrostatic and ion-dipole interactions
together with H bonds are responsible for the building up of the crystals.
104.
Linear oligopeptides. CXLII. Molecular structure of peptaibol antibiotics:
solution conformation and crystal structure of the octapeptide
corresponding to the 2-9 sequence of emerimicins III and IV. Toniolo,
Claudio; Bonora, Gian Maria; Bavoso, Alfonso; Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo. Journal of Biomolecular
Structure & Dynamics (1985), 3(3), 585-98.
Abstract: The IR absorption and 1H NMR of title peptide sequence pBrC6H4CO-(Aib)3-Val-Gly-Leu-(Aib)2-OMe (I, Aib = NHCMe2CO) in
CHCl3 indicated a 310-helical structure of high thermal stability. The crystal
structure of I indicated the formation of a right-handed 310-helix stabilized
by 6 consecutive intramol. NH...OC H bonds, slightly distorted at the level
of the Leu residue.
105.
Long polypeptide 310-helixes at atomic resolution. Bavoso, Alfonso;
Toniolo, Claudio; Bonora, Gian Maria. Proceedings of the National Academy of
Sciences of the United States of America (1986), 83(7), 1988-92.
Abstract: The crystal-state preferred conformation of the terminally blocked
homooctapeptide of Cα,α-dimethylated α-aminoisobutyric acid (Aib),
pBrBz(Aib)8-OBut (where pBrBz is p-bromobenzoyl and OBut is tertbutoxy), detd. by x-ray diffraction anal. using direct methods, was a 310helix stabilized by 6 consecutive intramol. N-H⋅⋅⋅O=C H bonds of the C10III (or III') type. This is the 1st observation at at. resoln. of a regular 310helix longer than 2 complete turns. The solid-state structural anal. was
extended to the terminally blocked, Aib-rich octapeptide corresponding to
the 2-9 sequence of the peptaibol antibiotics emerimicins III and IV, pBrBzAib3-L-Val-Gly-L-Leu-Aib2-OMe. Again, this peptide adopts a (righthanded) 310-helical structure, although slightly distorted at the level of the
L-leucine residue. The role of specific amino acid sequence and peptide
main-chain length in stabilizing either the 310- or the α-helical conformation
and their possible implications on the nature of the channel formed by
peptaibol antibiotics in the membrane are also briefly discussed.
93
106.
Linear oligopeptides: peptaibol antibiotics - preferred conformation of the 29 segment of emerimicins III and IV and all related short sequences.
Toniolo, Claudio; Bonora, Gian Maria; Benedetti, Ettore; Bavoso, Alfonso;
Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo. International Journal
of Biological Macromolecules (1985), 7(6), 357-62.
Abstract: With the aim of obtaining information on the effect induced by
main-chain length and amino acid sequence on the type of helical structure
adopted by naturally occurring peptides rich in Cα,α-dialkylated residues,
an IR absorption and 1H NMR anal. of CHCl3 solns. of the protected 2-9
segment of the peptaibol antibiotics emerimicins III and IV (-(Aib)3-L-ValGly-L-Leu-(Aib)2-) (Aib = aminoisobutyrate) and all related short
sequences starting from both the N- and C-termini was performed. The
results are consistent with the presence of folded structures of the β-bend
type (in the shorter peptides) or 310-helixes (in the longer peptides). Extent
of formation and stability of the inter- and intramol. H bonds were assessed
as a function of concn., temp., and addn. of DMSO and the free radical
Tempo. At high peptide concn. both folded and helical structures tend to
self-assoc. extensively. In the self-assocn. process, the N(1)H and N(2)H
groups are those acting as H-bonding donors. These results agree well with
those obtained in the solid state by x-ray diffraction on the octapeptide
itself and selected short sequences.
107.
A long, regular polypeptide 310-helix. Toniolo, C.; Bonora, G. M.; Bavoso,
A.; Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C. Macromolecules
(1986), 19(2), 472-9.
Abstract: The IR absorption and 1H NMR spectral analyses of CHCl3 solns.
of the terminally blocked homooctapeptide from the Cα,α-dimethylated αaminoisobutyric acid residue were consistent with the presence of a 310helical structure of high thermal stability. The crystal structure of the
octapeptide, obtained by x-ray diffraction, indicated the formation of a 310helix, stabilized by 6 consecutive intramol. N-H⋅⋅⋅O:C H-bonds of the C10III (or -III') type. This represents the 1st observation at at. resoln. of a
regular 310-helix larger than 2 complete turns. The packing of the
octapeptide mols. gives rise to a channel in which the solvent (MeOH and
H2O) mols. are accommodated.
108.
Conformational behavior of α,α-dialkylated peptides. Barone, Vincenzo;
Lelj, Francesco; Bavoso, Alfonso; Di Blasio, Benedetto; Grimaldi, Patrizio;
Pavone, Vincenzo; Pedone, Carlo. Biopolymers (1985), 24(9), 1759-67.
Abstract: The preferred conformations of N-acetyl-N'-Me amides of some
94
dialkylglycines were detd. by empirical conformational-energy calcns.;
min.-energy conformations were located by minimizing the energy with
respect to all the dihedral angles of the mols. The conformational space of
these compds. is sterically restricted, and low-energy conformations are
found only in the regions of fully extended and helical structures. On
increasing the bulkiness of the substituents on the Cα atom, the fully
extended conformation becomes gradually more stable than the helical
structure preferred in the cases of dimethylglycine. This trend is, however,
strongly dependent on the bond angles between the substituents on the Cα
atom: In particular, helical structures are favored by std. values (111°) of the
N-Cα-C' angle, whereas fully extended conformations are favored by
smaller values of the same angle, as exptl. obsd., for instance, in the case of
α,α-di-n-propylglycine.
109.
Linear oligopeptides - effect of lengthening of the main chain by one
tetrahedral carbon atom in the Aib-L-Ala- sequence: a solid-state
conformational analysis of segments of polypeptide antibiotics. Benedetti,
Ettore; Bavoso, Alfonso; Di Blasio, Benedetto; Grimaldi, Patrizio; Pavone,
Vincenzo; Pedone, Carlo; Toniolo, Claudio; Bonora, Gian Maria.
Abstract: The IR and x-ray diffraction conformational anal. of Boc-Aib-LAla-Aib-OMe (Boc = Me3CO2C, Aib = NHCMe2CO) showed the presence
of the type-I 4 → 1 intramolecularly H-bonded peptide conformation (βbend) in the solid state. Lengthening the chain by one tetrahedral carbon
atom, as in Boc-Aib-β-Ala-Aib-OMe, has a disruptive effect on this folded
structure. Two water mols. co-crystallize with each mol. of the L-Ala contg.
tripeptide. These results are discussed in comparison with those, previously
reported, obtained in chloroform soln.
110.
Dipeptides as inhibitors of the gelation of sickle hemoglobin. Noguchi,
Constance Tom; Luskey, Kenneth L.; Pavone, Vincenzo. Molecular
Pharmacology (1985), 28(1), 40-4.
Abstract: To examine in detail a class of peptides that inhibit the polymn. of
deoxygenated Hb S [9035-22-7], L-amino acids and 22 dipeptides were
assayed for their effect on deoxyHb S soly. Of the amino acids, the aroms.
(phenylalanine [63-91-2], tyrosine [60-18-4], and tryptophan [73-22-3])
increased deoxyHb S soly., as did high concns. of arginine [74-79-3].
Combinations of the hydrophobic (specifically the arom.) amino acids with
a hydrophilic amino acid, such as arginine or lysine [56-87-1], resulted in
dipeptides which were much more sol. than the hydrophobic or arom.
amino acid alone, and also inhibited polymn. Furthermore, samples of
95
deoxyHb S at 26 to 27 g/dL contg. some of these dipeptides such as Arg-Trp
[25615-38-7], Arg-Phe [2047-13-4], and Lys-Trp [50674-18-5] in excess of 50 to
100 mM did not polymerize, indicating a 1.4- to 1.6-fold increase in deoxyHb
S soly. The enhancement of polymn., i.e., decrease in deoxyHb S soly.,
obsd. by the addn. of aspartic acid [56-84-8], glycine [56-40-6], or lysine was
obsd. or was reduced in the dipeptides contg. these hydrophilic amino acids
combined with hydrophobic amino acids. The effects of these dipeptides on
deoxyHb S soly. were mostly linear with concn. However, the changes in
deoxyHb S soly. by addn. of a dipeptide was not simply the sum of the
effects obsd. with the individual amino acids as exemplified by the
differential effect of reversing the dipeptide sequence. These data provide
further evidence as to the stereospecific nature of this class of noncovalent
inhibitors of deoxyHb S polymn.
111.
Conformation of pleionomers of α-aminoisobutyric acid. Toniolo, Claudio;
Bonora, Gian Maria; Barone, Vincenzo; Bavoso, Alfonso; Benedetti, Ettore;
Di Blasio, Benedetto; Grimaldi, Patrizio; Lelj, Francesco; Pavone, Vincenzo;
Pedone, Carlo. Macromolecules (1985), 18(5), 895-902.
Abstract: The IR spectra and 1H NMR of the peptides
PhCH2OCO[NHC(Me)2CO]nOBu-tert (n = 1-12) indicates the formation
of fully developed, stable 310 helices for those with n = 8-12 (pleionomers).
Spectra were studied in the solid state, and in CDCl3 as a function of
concn., temp., and addn. of DMSO and the radical 2,2,6,6tetramethylpiperidinyl-1-oxyl. The mode of self-assocn. of the helical
structures was detd. A theor. study of AcNMC(Me)2COHNMe [42037-263] by conformational energy calcn. indicates that the fully extended
structure is less stable than the helical structures, regardless of the size of
the N-Cα-C' valence angle.
112.
Structure
of
dichloro[1,2-ethanedione
bis(dimethylhydrazone)](ηethylene)platinum(II), [PtCl2(C2H4)(C6H14N4)]. Bavoso, A.; Funicello,
M.; Morelli, G.; Pavone, V. Acta Crystallographica, Section C: Crystal
Structure Communications (1984), C40(12), 2035-7.
Abstract: The title compd., is monoclinic, space group P21, with a 8.998(3), b
8.133(4), c 9.872(2) .ANG., and β 106.72(3)°; dm = 2.09 and dc = 2.094 for R =
0.050 and Rw = 0.057 for 1404 reflections. At. coordinates are given. The
compd. has a trigonal-bipyramidal structure with the Cl atoms in apical
positions and the bidentate ligand (which coordinates through its α-diimine
units) and ethylene in the equatorial plane. The bidentate ligand is in a cis
conformation with some distortion from planarity. The Pt-Cl and Pt-olefin
bond distances are usual for 5-coordinate complexes of PtII.
96
113.
Folded and extended structures of homooligopeptides from α,α-dialkylated
glycines. A conformational energy computation and x-ray diffraction study.
Benedetti, Ettore; Toniolo, Claudio; Hardy, Paul; Barone, Vincenzo;
Bavoso, Alfonso; Di Blasio, Benedetto; Grimaldi, Patrizio; Lelj, Franceso;
Pavone, Vincenzo; et al. Journal of the American Chemical Society (1984),
106(26), 8146-52.
Abstract: Conformational energies were calcd. for Ac-(NHCPr2CO)nNHMe (I, n = 1, 2) and Ac-D-Iva-NHMe (II, Iva = isovaline residue) and
the results were compared to literature data for AcNHCMe2CONHMe
(III). The min. energy conformations of I correspond to fully extended
conformations, and a comparison with II and III indicated that the
preference from a folded to a fully extended conformation increases with
increasing bulkiness of the Cα-substituents. Theor. results agreed with
conformational properties in the solid state as detd. by x-ray diffraction.
114.
Folded and extended structures of homooligopeptides from α,α-dialkylated
α-amino acids. An infrared absorption and proton nuclear magnetic
resonance study. Bonora, Gian Maria; Toniolo, Claudio; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Benedetti, Ettore; Lingham,
Ian; Hardy, Paul. Journal of the American Chemical Society (1984), 106(26),
8152-6.
Abstract: The conformational preferences of Tfa-(NHCPr2CO)n-OCMe3
(Tfa = CF3CO, n = 2-5) in the solid state and in CHCl3 soln. were assessed
by IR and 1H NMR. A comparison is made with the conformations adopted
by the corresponding series from α-aminoisobutyric acid, also dialkylated at
the α-carbon, and from L-norvaline, in which the single alkyl side chain is
the same as those in α,α-di-n-propylglycine. The highest L-norvaline
homopeptides exhibit a significant tendency for adopting an
intermolecularly H-bonded β-structure, in contrast to the α,α-di-npropylglycine and α-aminoisobutyric acid peptides where intramol. Hbonding is the dominating factor. The likely absence of a conformational
transition with increasing chain length and the exceptional structural
stability upon heating of all the α,α-di-n-propylglycine homopeptides
represent an addnl. relevant finding.
115.
Modified calmodulin calcium binding domain III. Solid phase synthesis,
purification and proton NMR characterization. Pavone, Vincenzo; Di Nola,
Angela; Andini, Salvatore; Ferrara, Luciano; Di Blasio, Benedetto;
Benedetti, Ettore; Pucci, Piero. International Journal of Peptide & Protein
97
Research (1984), 23(5), 454-61.
Abstract: Title dodecapeptide Ac-Asp-Lys-Asp-Gly-Asn-Gly-Tyr-Ile-SerAla-Ala-Gaba-OH [I, Gaba = NH(CH2)3CO] was prepd. by the solid
phase method with a total protection scheme using PAM-resin. Purified I
was characterized by 1H NMR spectroscopy, both in the presence and in the
absence of calcium ions at various pH values. No strong specific interaction
occurred between I and Ca2+ in aq. solns.
116.
Studies on gliadin related peptides. I. Synthesis, purification and proton
NMR characterization of the pentapeptide H-Tyr-(Gln)3-Pro-OH. Pavone,
V.; Rossi, F.; Pucci, P.; Andini, S.; Ferrara, L.; Di Blasio, B.; Pedone, C.
Abstract: The title pentapeptide (I) was prepd. by the solid-phase method on
the PAM-resin. I was characterized by its NMR. I has been postulated as
the basic repetitive unit of a sequential polypeptide contained in wheat
bread α-gliadins, which could be the toxic factors in coeliac disease.
117.
Protected 1-3 segment of the peptaibol antibiotics alamethicin and hypelcin.
Solid-state and solution study of a stereochemically constrained linear
peptide. Benedetti, Ettore; Bavoso, Alfonso; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo; Toniolo, Claudio; Bonora, Gian Maria; Crisma,
Marco. International Journal of Peptide & Protein Research (1983), 22(4), 385-97.
Abstract: Title peptide PhCH2O2C-Aib-Pro-OMe (Aib = NHCMe2CO)
was prepd. and its modes of folding and self-assocn. in the solid state were
detd. using IR absorption and x-ray diffraction. Stereochem.-constrained
tripeptide mols. adopt a 4 → 1 intramol. H-bonded form (β-turn), where the
single intramol. H bond is found between the peptide NH group of the Aib3
residue and the urethane CO group of the N-blocking benzyloxycarbonyl
moiety. This folded structure is stabilized by an intermol. H bond between
the urethane NH group of the Aib1 residue and the peptide CO group of the
Pro2 residue of a symmetry related mol. In CH2Cl2 and TMP solns. the
same intramol. H bonded form occurs as that found in solid state.
Compared to the solid state, CH2Cl2 and TMP solvation of the urethane
NH group replaces self-assocn. (through the same NH group). The results
are discussed in relation to those obtained for other protected -Aib-X-Aib(X = Aib, Ala, Val) tripeptide segments of peptaibol antibiotics.
118.
Bioorganic stereochemistry. A study of the peptide oxazolones from Z(Aib)n-OH (n = 2-4) in the solid state. Toniolo, Claudio; Bonora, Gian
Maria; Crisma, Marco; Benedetti, Ettore; Bavoso, Alfonso; Di Blasio,
98
Benedetto; Pavone, Vincenzo; Pedone, Carlo. International Journal of Peptide
& Protein Research (1983), 22(5), 603-10.
Abstract: The conformations and modes of self-assocn. of title oxazolones
(Z = PhCH2O2C, Aib = NHCMe2CO) in the solid state were detd. by IR
spectroscopy. The structure of oxazolone from Z-(-Aib-)3-OH was obtained
by x-ray diffraction. In this compd. the conformations of the first two Aib
residues differ substantially, only the N-terminal one was in the usual 310
(or α) helical region of the Ramachandran map. The C:N bond of the
oxazolone group is not conjugated with the lactone moiety. A very weak
intermol. interaction occurs between the urethane NH and the carbonyl
group of the oxazolone ring.
119.
Structure
of
N-tert-butyloxycarbonyl-D-leucyl-Lphenylalanylethanolamide. An Nα-protected analog of the carboxy-terminal dipeptide of
linear gramicidins. Bonora, Gian Maria; Toniolo, Claudio; Bavoso, Alfonso;
Benedetti, Ettore; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo.
Journal of Biological Chemistry (1983), 258(23), 14725-32.
Abstract: Solid state conformational anal. of N-tert-butyloxycarbonyl-Dleucyl-L-phenylalanylethanolamide (I) an Nα-protected analog of the Cterminal dipeptide of linear gramicidins, carried out by x-ray diffraction,
has indicated that the mols. are characterized by an N-H...O:C
intramolecularly H-bonded chain reversal of the β-turn II' type. One of the
2 independent mols. in the asym. unit shows an addnl. intramol. H bond of
the O-H...O:C type, linking the hydroxyl function of the C-terminal
ethanolamide moiety to the carbonyl O of the urethane N-protecting group.
This is the 1st exptl. evidence for a β-turn conformation fused with the oxy
analog of an α-turn. The results of an investigation in a solvent of low
polarity (deuteriochloroform), using IR absorption and 1H NMR strongly
support the view that an intramolecularly H-bonded β-turn conformation is
the most populated conformation of I mols. at high diln. In the self-assocn.
process, taking place at high concn., the urethane and peptide NH groups
are involved as H-bonding pairs.
120.
Linear oligopeptides. 90. Peptaibol antibiotics: conformational preferences
of synthetic emerimicin fragments. Toniolo, Claudio; Bonora, Gian Maria;
Benedetti, Ettore; Bavoso, Alfonso; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo. Biopolymers (1983), 22(5), 1335-56.
Abstract: The IR absorption and CD conformational analyses of solns. of
the protected 2-9 fragment of the peptaibol antibiotics emerimicins III and
IV, -(Aib)3-Val-Gly-(Aib)2- (Aib = NHCMe2CO), and related short
99
sequences are consistent with the presence of a right-handed α-helix for the
octapeptide, while the tri-, tetra-, and pentapeptides adopt a 310-helix, either
right- or left-handed, depending on the amino acid sequences. The
structural preferences of solid-state Z(Aib)-Val-OMe (Z = PhCH2O2C)
and Z(Aib)-Val-Gly-OMe were detd. by x-ray diffraction. In accord with
the soln. data. incipient 310-helices, formed by 2 and 3 β-turns, were found
for the tetra- and pentapeptides, resp. The tetrapeptide helix has the lefthanded screw sense, while that of the pentapeptide is right-handed, thus
confirming the conclusions of the CD anal. in soln.
121.
First observation of a β -turn conformation fused with the oxy-analog of an
α -turn: the molecular structure of a model peptide of the C-terminal part of
gramicidin A. Benedetti, Ettore; Bavoso, Alfonso; Di Blasio, Benedetto;
Pavone, Vincenzo; Pedone, Carlo; Toniolo, Claudio; Bonora, Gian Maria.
Biochemical and Biophysical Research Communications (1983), 112(3), 1056-60.
Abstract: The mol. structure of Me3CO2C-D-Leu-Phe-NHCH2CH2OH, a
protected analog of the C-terminal dipeptide of gramicidin A, was detd. by
x-ray diffraction. One of the two independent mols. in the asym. unit is
characterized by a chain reversal stabilized by intramol., three-center,
double hydrogen bonding. This is the first exptl. evidence for a β-turn
conformation fused with the oxy-analog of an α-turn.
122.
Structure and conformation of regularly alternating LD linear peptides.
Pedone, Carlo; Benedetti, Ettore; Di Blasio, Benedetto; Mattia, Carlo
Andrea; Morelli, Giancarlo; Pavone, Vincenzo; Lorenzi, Gian Paolo;
Gerher, Christofer. Biopolymers (1983), 22(1), 323-5.
Abstract: Boc(L-Val-D-Val)4OMe (Boc = Me3CO2C) was shown by x-ray
anal. to have a dimeric left-handed β-structure stabilized by 14 interstrand
H bonds. Boc(D-Phe-L-Phe)4OMe has a similar structure. Boc(D-allo-IleL-Ile)OMe has a chain-reversed structure, stabilized by multiple intramol.
H bonds, in which a β-turn is fused to an α-turn.
123.
Solid-state geometry and conformation of linear, diastereoisomeric
oligoprolines. Benedetti, Ettore; Bavoso, Alfonso; Di Blasio, Benedetto;
Biopolymers (1983), 22(1), 305-17.
Abstract: The solid-state conformation preferences of a no. of linear
homooligoprolines (to the tetramer) were detd. by anal. of IR and x-ray
data. The peptides present different chiral sequences (tacticities), various
types (urethane and amide) of N-protecting groups, and free and
100
blocked C-termini (which imply different capabilities of forming H-bonds).
The following conclusions can be drawn: (1) values for the geometry of the
prolyl residue and the peptide bond in the cis and in the trans
conformations are proposed; (2) in general the conformational angles φ and
ψ in the linear homooligoprolines have values appropriate for the
polyproline II structure; (3) the pyrrolidine ring shows various types of
puckering with no apparent relation to the backbone conformation; (4) ProPro peptide bonds generally take the trans conformation, the few cases of
cis conformation being formed by Pro residues of different chirality; (5) the
single H-bond donor OH, when present, is always bonded to H-acceptors,
which can be either the urethane or the amide or the peptide carbonyl but
never the carbonyl group of the CO2H moiety.
124.
Linear oligopeptide. Part 87. Conformation of linear homooligoprolines.
VII. N-Pivaloyl-L-prolyl-D-proline methyl ester in the solid state.
Benedetti, Ettore; Bavoso, Alfonso; Di Blasio, Benedetto; Pavone,
Abstract: A conformational anal. of Me3CCO-L-Pro-D-Pro-OMe was
performed in the solid state using IR absorption and x-ray diffraction. The
tertiary amide bond is in the trans conformation, whereas the tertiary
peptide bond is in the cis conformation. The preferred conformations of the
pivaloylamino group, the pyrrolidine rings, and the ester moiety are also
discussed.
125.
Peptaibol antibiotics: a study on the helical structure of the 2-9 sequence of
emerimicins III and IV. Benedetti, Ettore; Bavoso, Alfonso; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Toniolo, Claudio; Bonora,
Gian Maria. Proceedings of the National Academy of Sciences of the United
States of America (1982), 79(24), 7951-4.
Abstract: Soln. conformations of the protected 2-9 segment of the peptaibol
antibiotics emerimicins III and IV [α-aminoisobutyric acid (Aib)]3-L-ValGly-L-Leu-(Aib)2 and the related short sequences benzyloxycarbonyl(Aib)3-L-Val-OMe and benzyloxycarbonyl-(Aib)3-L-Val-Gly-OMe have
been investigated by CD studies. For the latter 2 compds. the structural
preferences in the solid state have been assayed by x-ray diffraction
analyses. These data and those previously reported support the view that
the shortest Aib-contg. segments (from tri- through pentapeptides) adopt
the 310-helical structure both in soln. and in the solid state. In contrast, the
octapeptide appears to adopt the α-helical structure in soln. The role of
peptide chain length and specific amino acid sequences in stabilizing either
101
of the 2 helical structures and, hence, their possible implications on the
nature of the channel formed by peptaibol antibiotics in the membrane are
also briefly outlined.
126.
A hairpin-shaped peptide conformation stabilized by multiple
intramolecular hydrogen bonds for a linear alternating D,L hexapeptide.
Bavoso, Alfonso; Benedetti, Ettore; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo; Lorenzi, Gian Paolo; Muri-Valle, Valentina.
Biochemical and Biophysical Research Communications (1982), 107(3), 910-13.
Abstract: A linear hexapeptide with alternating D,L residues,
butoxycarbonyl-(D-alloIle--L-Ile)3-OMe (alloIle = alloisoleucine), which in
the solid state give rise to a chain reversal stabilized by multiple intramol.
H bonds, was conformationally characterized by x-ray anal. This is the 1st
description of a β-turn (C10) and an α-turn (C13) fused together and
included in a larger 17-membered ring occurring in a linear peptide.
127.
Linear oligopeptides. 81. Solid-state and solution conformation of
homooligo(α-aminoisobutyric acids) from tripeptide to pentapeptide:
evidence for a 310 helix. Benedetti, Ettore; Bavoso, Alfonso; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Crisma, Marco; Bonora, Gian
Maria; Toniolo, Claudio. Journal of the American Chemical Society (1982),
104(9), 2437-44.
Abstract: Anal. of the x-ray diffraction and IR absorption data for
PhCH2O2C(NHCMe2CO)nOR (I; R = CMe3, n = 3, 5; R = H, n = 4)
showed the occurrence of incipient 310 helices formed by type III (or type
III') β-turns. The intramol. NH to CO H-bonding schemes of I (n = 4, 5)
are not compatible with α-helical structures. The IR of I in solvents of low
polarity indicated the occurrence of the same intramol. H-bonded forms as
found in the solid state. These structures undergo aggregation at high
concns. The 310-helical structure must be considered when developing a
model of folding for alamethicin.
128.
Linear oligopeptides. Part 85. Preferred conformations of linear
homooligoprolines. N-tert-butyloxycarbonyl-D-prolyl-D-prolyl-L-proline.
Bavoso, Alfonso; Benedetti, Ettore; Di Blasio, Benedetto; Pavone,
Macromolecules (1982), 15(1), 54-9.
Abstract: The title peptide (I) was prepd. and its solid-state and soln.
conformations were detd. by x-ray diffraction and IR absorption. In the
solid state, the mols. of I do not form an intramol. H-bonded oxy-C10
102
peptide conformation, but they are held together by intermol. H bonds
between the peptide carbonyl of D-Pro1-D-Pro3 and the carboxyl OH. For
concn. solns. of I in solvents of low polarity, the type of assocn. is different
than that in the solid state, whereas in dil. solns. there is no onset of
intramol. H bonding. In solvents with strong H-bonding acceptor and
donor properties, only solvated species of I exist.
129.
Structure of N-acetyl-D-alanyl-D-alanine hydrate. An analog of the
carboxy-terminal segment of peptidoglycan of bacterial cell walls.
Toniolo, Claudio; Bonora, Gian Maria. Journal of Biological Chemistry (1981),
256(17), 9229-34.
Abstract: The solid state conformational anal. of Ac-D-Ala-D-AlaOH.H2O, carried out by IR absorption and x-ray diffraction, has indicated
that the mols. are not extended in a regular β conformation, but rather that
they are partially folded, the ϕ,ψ* torsional angles of the C-terminal residue
in particular being in the region of the left-handed α helix of the
Ramachandran map. The acetylamino and peptide groups are found in the
usual trans conformation, the latter, however, exhibiting a deviation from
rigid planarity. Only intermol. H bonds occur in the crystal state. The soln.
conformational anal., performed by IR absorption and CD, has revealed that
the amt. of intramol. N-H...O:C hydrogen-bonded folded forms, if any,
should be extremely small, even in C2HCl3 at high diln. In water, solvated,
unordered species largely predominate.
130.
Self-association of N-protected α-amino acids. Optically active and racemic
N-tert-butyloxycarbonyl-alanine. Benedetti, Ettore; Di Blasio, Benedetto;
Biopolymers (1981), 20(8), 1635-49.
Abstract: The IR absorption and x-ray diffraction anal. of N-tertbutyloxycarbonyl-DL-alanine (t-Boc-DL-Ala-OH) in the solid state has
revealed a new mode of self-assocn. for a N-urethanyl-α-amino acid, i.e.,
ribbons of H-bonded cyclic dimers formed through the COOH groups. In
contrast to the racemate, a water mol., incorporated into the crystal of the
chiral t-Boc-D-Ala-OH, alters in part that H-bonding scheme. In the 2
independent mols. of the unit cell of the optically active alanine deriv., as in
that of the racemic deriv.: (1) the conformation of the CONH group is
trans, and (2) the overall conformation is quasi-extended. These findings
exclude the occurrence of an oxy-C7 peptide conformation. In solvents of
high polarity, strongly solvated species predominate, as shown by IR
absorption spectroscopy. In CDCl3 nonassocd. and assocd. species occur
103
simultaneously. No differences were obsd. between the optically active and
racemic derivs. The type of self-assocn. near satn. seems to differ, at least in
part, from that found in the anhyd. racemic compd. in the crystal state.
131.
Conformational studies of peptides: crystal and molecular structures of L3,4-dehydroproline and its tert-butoxycarbonyl and acetyl amide
derivatives. Benedetti, Ettore; Di Blasio, Benedetto; Pavone, Vincenzo;
Pedone, Carlo; Felix, Arthur; Goodman, Murray. Biopolymers (1981), 20(2),
283-302.
Abstract: The crystal structure of the title compds. were detd. by x-ray data;
3,4-dehydroproline exists as the zwitterion in the cryst. state. The
conformations of the 2 amide derivs. have 2 planes: one for the primary
amide and the other for the remaining atoms of the mol. Acetyl-3,4dehydroproline amide contains a tertiary amide bond in the cis
conformation. Both amide derivs. have φ and ψ values corresponding to a
collagen-like conformation.
132.
Linear oligopeptides. 65. Conformational analysis of the N-protected
aromatic α -amino acid N-tert-butyloxycarbonyl-L-phenylalanine by x-ray
diffraction and infrared absorption. Benedetti, Ettore; Di Blasio, Benedetto;
Abstract: The x-ray diffraction and IR absorption conformational anal. of
N-tert-butyloxycarbonyl-L-phenylalanine showed the absence of
intramolecularly H-bonded peptide conformations in the solid state. The
mols. are held together in rows of cyclic dimer motifs through intermol. NH...O:C(acid) and O-H...O:C (urethane) H bonds, the secondary amidelike group of the urethane moiety being in the unusual cis conformation,
whereas the COOH group in the common syn conformation. The 2 mols.
in the unit cell present a centrosym. set of ϕ, ψ1, and ψ2 values. In polar
solvents, solvated species largely predominate. In satd. hydrocarbon soln.,
nonassocd. and assocd. (mostly involving the carboxylic acid C:O as the
proton acceptor) species simultaneously occur. The extent of assocn.
decreases with diln. The amt. of intramolecularly H-bonded oxy-C7 and C5
forms if any, should be extremely small. The type of assocn. at satn.
apparently differs from that found in the cryst. compd. obtained by pptn.
with satd. aliph. hydrocarbons (from a Et2O soln.).
133.
Conformations of diastereoisomeric peptides. N-(tert-butyloxycarbonyl)-Lprolyl-D-proline and its methyl ester in the solid state and in solution.
104
Toniolo, Claudio; Bonora, Gian Maria. Macromolecules (1980), 13(6), 1454-62.
Abstract: X-ray diffraction and IR data showed that the solid-state
conformations of Me3CO2C-Pro-D-Pro-OR (I; R = H, Me) have a cis
tertiary urethane bond and a trans tertiary amide bond. The mols. of I (R =
H) in the solid state are linked by an intermol. OH...OC (urethane) H
bond. The conformations of I in soln. were also detd. In solvents of high
polarity, solvated species predominate. For I (R = H), even in a solvent of
low polarity at high diln., the extent of intramol. H bonding was small.
134.
Conformational analysis of N-(tert-amyloxycarbonyl-L-proline in the solid
state and in solution. Benedetti, Ettore; Ciajolo, Anna; Di Blasio, Benedetto;
Abstract: X-ray and IR data showed that the mols. of the title compd. (I) in
the solid state are not folded into an oxy-C7 peptide conformation, but are
held together through intermol. urethane H bonds, and the tertiary amide
bond has the cis configuration. CO and IR data showed that strongly
solvated species predominate for I in highly polar solvents. In cyclohexane
nonassociated and assocd. species of I are simultaneously present and the
amt. of oxy-C7 form is extremely small. CD measurements alone can lead
to an incorrect conformation of amino acid derivs. and small peptides in
soln.
135.
Structure and conformation of peptides: N-benzyloxycarbonyl-(γ -ethyl)-Lglutamyl-(γ -ethyl)-L-glutamic acid ethyl ester. Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Germain, Gabriel; Goodman,
Murray. Biopolymers (1979), 18(3), 517-22.
Abstract: The crystal structure of the title compd. was detd. The urethane
and amide bonds and all ester groups are in the trans configuration, and the
Φ and ψ angles of the glutamyl residue fall in the β-structure region of the
Ramachandran plot. The mol. is flat with the amide plane almost parallel to
the c axis along which 2 H bonds hold the mols. together in a parallel
pleated sheet.
136.
Linear oligopeptides. 59. Stereochemical analysis of N-tertbutyloxycarbonyl-L-prolylsarcosine
and
N-tertbutyloxycarbonylsarcosylsarcosine in the solid state and in solution.
Benedetti, Ettore; Ciajolo, Anna; Di Blasio, Benedetto; Pavone, Vincenzo;
Pedone, Carlo; Toniolo, Claudio; Bonora, Gian Maria. Macromolecules
(1979), 12(3), 438-45.
105
Abstract: The conformation of the title peptides in the solid state and in
soln. were analyzed by IR and x-ray diffraction data. In the solid state, a cistert-urethane bond and an intermol. H bond between the OH of the CO2H
and an amide O characterized the mol. and crystal structure. In soln. the
formation of intramol. H bonds was negligible, even in a solvent of low
polarity and high diln.
137.
L-Methionine hydrochloride. De Blasio, B.; Pavone, V.; Pedone, C. Crystal
Structure Communications (1977), 6(4), 845-8.
Abstract: Mols. of the title compd. are disposed in crystals according to the
general mode of packing for this type of mol. The conformation of the side
chain moiety is different from that of the same group in α and β forms of
free DL-methionine. The mol. is more compact as the HCl salt due to the
presence of a gauche bound around the C2-C3 atoms, whereas this rotation
angle is trans in the α and β forms.
138.
Glycine hydrochloride C2H5NO2.HCl [and] L-alanine hydrochloride
C3H7NO2.HCl. Di Blasio, B.; Pavone, V.; Pedone, C. Crystal Structure
Communications (1977), 6(4), 745-8.
Abstract: The crystal structures of the title compds. consist of layers contg.
Cl- and the appropriate amino acid ammonium ion in which the Cl- forms 2
H bonds with N atoms and 1 H bond with an O-H group. This is the usual
packing of mols. for crystals of anhyd. amino acid hydrochlorides with a
non-polar side chain.
139.
Solid-state and solution conformation of N-tert-butyloxycarbonyl-Lprolylglycine. Benedetti, E.; Pavone, V.; Toniolo, C.; Bonora, G. M.;
Palumbo, M. Macromolecules (1977), 10(6), 1350-6.
Abstract: The proposed folding of the title compd. (I) in the solid state to
form an intramol. H-bonded 10-membered oxy analog of the trans II β turn,
which was based on IR data, was rejected on x-ray detn. The low-frequency
value of the urethane CO stretching vibration in the IR spectrum of I in the
solid state can be explained by intermol. H bonds. This type of intramol.
folding is also absent in polar solvents; a strong neg. Cotton effect at 225 nm
in the CO of I in solvents of low polarity could be due to this type of
folding.
140.
N,N'-bis(β -chloroethyl)pimelamide. Ciajolo, M. R.; Pavone, V.; Benedetti,
E. Acta Crystallographica, Section B: Structural Crystallography and Crystal
106
Chemistry (1977), B33(4), 1295-7.
Abstract: The title compd. is monoclinic, space group P21, with a 4.941(5), b
32.425(30), c 4.817(5) .ANG., and β 113°37(5)'; d.(calcd.) = 1.331 for Z = 2. The
mol. conformation is not fully extended. Each mol. forms H bonds along
two directions (almost the a and c directions). A comparison with N,N'bis(β-chloroethyl)glutaramide is made.
141.
Bis(n-dodecylammonium) tetrachlorozincate. Ciajolo, M. R.; Corradini, P.;
Pavone, V.. Acta Crystallographica, Section B: Structural Crystallography and
Crystal Chemistry (1977), B33(2), 553-5.
Abstract: The title compd. is monoclinic, space group P21/c, with a 7.409(3),
b 10.379(5), c 44.399(10) .ANG., and β 105.56(5)°; d.(calcd.) = 1.159 for Z = 4.
The structure is characterized by ionic layers sandwiched between layers of
paraffinic chains.
142.
Comparative studies of layer structures: the crystal structure of
bis(monodecylammonium)tetrachloromanganate(II). Ciajolo, Maria R.;
Corradini, Paolo; Pavone, Vincenzo. Gazzetta Chimica Italiana (1976), 106(910), 807-16.
Abstract: The structure of the title compd. was detd. by x-ray diffraction,
solved by the Patterson method, and refined by least-squares calcns. to a R
of 0.086. The crystals are monoclinic, space group P21/a, with a 7.213(8), b
7.337(2), c 26.747(21) .ANG., and b 94.64(5)°; Z = 2. Bond lenghts and angles
are given and the mol. packing is discussed. The MnCl42- anion is
polymeric and has D4h symmetry. Individual anions are bridged by Cl
atoms. The NH3 groups are placed at the center above the squares formed
by 4 axial Cl atoms giving the Mn ions a square pyramidal conformation.
107
PROCEEDINGS
1.
Developing synthetic hemoprotein mimetics: design, synthesis and
characterization of heme-peptide conjugates. Lombardi, Angela; Nastri,
Flavia; D'Andrea, Luca D.; Maglio, Ornella; D'Auria, Gabriella; Pedone,
Carlo; Pavone, Vincenzo. Editor(s): Tam, James P.; Kaumaya, Pravin T. P.
Peptides: Frontiers of Peptide Science, Proceedings of the American Peptide
Symposium, 15th, Nashville, June 14-19, 1997 (1999), Meeting Date 1997, 9193. Publisher: Kluwer, Dordrecht, Neth.,
Abstract: A symposium with five refs. The properties of mimochrome II, a
hemoprotein model compd., were evaluated in relation to the peptide chain
compn. and length and its importance in controlling heme properties.
2.
A novel class of calmodulin mimetics: De novo designed proteins in
molecular recognition. Lombardi, Angela; Ghirlanda, Giovanna; Zaccaro,
Laura; Pavone, Vincenzo; DeGrado, William F. Editor(s): Tam, James P.;
Kaumaya, Pravin T. P. Peptides: Frontiers of Peptide Science, Proceedings
of the American Peptide Symposium, 15th, Nashville, June 14-19, 1997 (1999),
Meeting Date 1997, 94-96. Publisher: Kluwer, Dordrecht, Neth.,
Abstract: This symposium report describes the designing of an α-helical
dimer, covalently linked in a parallel or antiparallel orientation, that
specifically interacts with only one of the target enzymes recognized by
calmodulin (CaM). The chosen protein sequence was from the CaM
binding domain of calcineurin.
3.
Induced helical structure in highly charged peptides. Lombardi, A.; Zaccaro,
L.; Ansanelli, G.; Pedone, C.; Pavone, V.. Editor(s): Shimonishi,
Yasutsugu. Peptide Science: Present and Future, Proceedings of the
International Peptide Symposium, 1st, Kyoto, Nov. 30-Dec. 5, 1997 (1999),
Meeting Date 1997, 385-387. Publisher: Kluwer, Dordrecht, Neth.,
Abstract: A symposium on the properties and capacity of a synthetic highlycharged peptide (no data) to bind with a polynucleotide sequence contg. the
GCG recognition triplet.
4.
Miniaturized hemoproteins: a covalent asymmetric peptide-porphyrin
system. D'Andrea, Luca D.; Nastri, Flavia; Lombardi, Angela; Maglio,
Ornella; Pavone, Vincenzo. Editor(s): Bajusz, Sandor; Hudecz, Ferenc.
Peptides 1998, Proceedings of the European Peptide Symposium, 25th,
Budapest, Aug. 30-Sept. 4, 1998 (1999), Meeting Date 1998, 304-305.
108
Publisher: Akademiai Kiado, Budapest, Hung.,
Abstract: A symposium report. The solid-phase synthesis of a hemoprotein
mimetic, mimochrome III, is reported.
5.
Topology of porphyrins linked to de novo four-helix bundle proteins:
towards the design and synthesis of multicofactor redox enzymes. Rabanal,
Francesc; Lombardi, Angela; Pavone, Vincenzo; DeGrado, William F.;
Dutton, P. Leslie. Editor(s): Ramage, Robert; Epton, Roger. Peptides 1996,
Proceedings of the European Peptide Symposium, 24th, Edinburgh, Sept. 813, 1996 (1998), Meeting Date 1996, 741-742. Publisher: Mayflower Scientific,
Kingswinford, UK,
Abstract: A symposium report on the prepn. of a designed four-α-helix
bundle protein with histidine residues at selected locations for complexation
of a deuteroporphyrin residue to be attached to a defined lysine side chain.
6.
Rational design of enzymically resistant, peptide based, multi-site directed,
α -thrombin inhibitors. Lombardi, A.; Nastri, F.; Galdiero, S.; Della Morte,
R.; Staiano, N.; Pedone, C.; Pavone, V.. Editor(s): Kaumaya, Pravin T. P.;
Hodges, Robert S. Peptides: Chemistry, Structure and Biology, Proceedings
of the American Peptide Symposium, 14th, Columbus, Ohio, June 18-23, 1995
(1996), Meeting Date 1995, 374-375. Publisher: Mayflower Scientific,
Kingswinford, UK,
Abstract: A symposium report on the synthesis of hirudin analogs for use as
α-thrombin inhibitors.
7.
A novel strategy for the synthesis of heme-peptide conjugates. Nastri,
Flavia; Lombardi, Angela; Maglio, Ornella; Morelli, Giancarlo; D'auria,
Gabriella; Pedone, Carlo; Pavone, Vincenzo. Editor(s): Epton, Roger.
Innovation and Perspectives in Solid Phase Synthesis & Combinatorial
Libraries: Peptides, Proteins and Nucleic Acids--Small Molecule Organic
Chemical Diversity, Collected Papers, International Symposium, 4th,
Edinburgh, Sept. 12-16, 1995 (1996), Meeting Date 1995, 491-494. Publisher:
Mayflower Scientific, Birmingham, UK,
Abstract: A symposium report. We report here a novel strategy for the
synthesis of heme-peptide conjugates. This synthetic procedure allows the
synthesis of a wide variety of analogs made up of either two equal or
different peptide chains linked to the porphyrin ring.
8.
Conformation features of functionalized cyclodextrins: A ternary complex
109
of histamino β -cyclodextrin, copper(II) and L-tryptophan. Saviano, M.; Di
Blasio, B.; Pavone, V.; Pedone, C. Editor(s): Maia, Hernani L. S. Peptides
1994, Proceedings of the European Peptide Symposium, 23rd, Braga, Port.,
Sept. 4-10, 1994 (1995), Meeting Date 1994, 568-569. Publisher: ESCOM,
Leiden, Neth.,
Abstract: The structure of the ternary complex of 6-deoxy-6-N-histamino-βcyclodextrin, copper(II), and L-tryptophan (no prepn. given) has been
solved by direct methods in order to gain conformational information about
interactions responsible for chiral recognition of arom. amino acids by the
copper histamino-β-cyclodextrin receptor. Structure data: monoclinic space
group P21, a 15.145, b 17.296, c 16.420 .ANG., β 105.2°, Z = 2. One nitrate and 15
co-crystd. H2O mols. were detected in the unit cell. Both tryptophan and
the histamino β-cyclodextrin act as bidentate ligands. The Cu(II) ion
assumes a distorted pentacoordination in which two N atoms of the
histamino moiety and of the amide, and an O atom of the carboxyl group of
the L-amino acid, occupy the four square-planar positions. The remaining
apical position is occupied by a water mol.
9.
Structural requirements for antagonist activity at tachykinin NK2 receptor
in a series of bicyclic hexapeptides. Quartara, L.; Fabbri, G.; Patacchini, R.;
Maggi, C. A.; Astolfi, M.; D'Auria, G.; Maglio, O.; Lombardi, A.; Pedone,
C.; Pavone, V.. Editor(s): Maia, Hernani L. S. Peptides 1994, Proceedings of
the European Peptide Symposium, 23rd, Braga, Port., Sept. 4-10, 1994 (1995),
Meeting Date 1994, 591-592. Publisher: ESCOM, Leiden, Neth.,
Abstract: The authors describe here the conformational and configurational
requirements for the high affinity interaction of MEN 10627 with
tachykinin NK2 receptor. The remarkable differences in the antagonist
potencies shown by the peptides described herein are strictly related to their
different structures. Less active compds. are characterized by different
orientations of the amino acid side chains. In the homochiral sequences, the
bridge residues Asp2 and Dap5 are located in the i and i+3 positions of two
β-turns, while in the heterochiral sequences the bridge residues occupy the
i+2 positions of two β-turns. This shift of β-turn corner positions dets. a
completely different mol. shape and a dramatic drop in biol. activity.
10.
Specific interaction between cyclophilin and cyclic peptides. Gallo, P.;
Saviano, M.; Rossi, F.; Pavone, V.; Pedone, C.; Ragone, R.; Stiuso, P.;
Colonna, G. Editor(s): Maia, Hernani L. S. Peptides 1994, Proceedings of
the European Peptide Symposium, 23rd, Braga, Port., Sept. 4-10, 1994 (1995),
110
Abstract: Cyclolinopeptide A, a cyclic nonapeptide from linseed and its
synthetic analog CLAIB bind to bovine cyclophilin A and inhibit peptidylprolyl cis-trans isomerase activity. The dissocn. consts. and enzymic 50%
inhibition values of cyclolinopeptide A, CLAIB, and the
immunosuppressant cyclosporin A (which also binds with cyclophilin A).
11.
A new potent and highly selective, long lasting, peptide-based neurokinin A
antagonist: rational design of MEN 10627. Pavone, V.; Lombardi, A.;
Pedone, C.; Quartara, L.; Maggi. C. A. Editor(s): Hodges, Robert S.; Smith,
John A. Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp., 13th (1994),
Abstract: MEN 10627 is the prototype of a new class of cyclic peptide-based
NK-2 receptor antagonists. Owing to its high potency and long lasting
activity in vivo, MEN 10627 and its analogs are suitable candidates for clin.
testing in humans.
12.
β-cyclodextrins as potent bioactive peptide delivery systems. Rossi,
Filomena; Zaccaro, Laura; Di Blasio, Benedetto; Pavone, Vincenzo; Maglio,
Ornella; Saviano, Michele; Pedone, Carlo; Cucinotta, Vincenzo;
Impellizzeri, Giuseppe; et al. Editor(s): Schneider, Conrad H.; Eberle, Alex
N. Pept. 1992, Proc. Eur. Pept. Symp., 22nd (1993), Meeting Date 1992, 577-8.
Publisher: ESCOM, Leiden, Neth.,
Abstract: Solid-state studies on 6-deoxy-6-cyclo(L-histidyl-L-leucyl)-βcyclodextrin
and
6-deoxy-6-N-(2-methylhexahydropyrimidine)-βcyclodextrin complexes are reported.
13.
Molecular tools for the design of γ -turn in peptides. Pavone, V.; Lombardi,
A.; D'Auria, G.; Saviano, M.; Di Blasio, B.; Paolillo, L.; Pedone, C.
Editor(s): Smith, John A.; Rivier, Jean E. Pept.: Chem. Biol., Proc. Am.
Pept. Symp., 12th (1992), Meeting Date 1991, 366-7. Publisher: ESCOM,
Leiden, Neth.,
Abstract: A symposium report on the synthesis and structural
characterization both by NMR in CD3CN soln. and by x-ray diffraction of
the cyclic tetrapeptides cyclo(β-Ala-L-Pro-β-Ala-Aaa) (Aaa = L-Pro, L-Val)
in order to verify the usefulness of the sequence β-Ala-Pro-β-Ala as mol.
tool to force the peptide in a γ-turn conformation.
14.
The fully extended polypeptide conformation. Toniolo, C.; Valle, G.;
Crisma, M.; Benedetti, E.; Pedone, C.; Di Blasio, B.; Pavone, V.. Editor(s):
Smith, John A.; Rivier, Jean E. Pept.: Chem. Biol., Proc. Am. Pept.
111
Symp., 12th (1992), Meeting Date 1991, 276-7. Publisher: ESCOM, Leiden,
Neth.,
Abstract: A report from a symposium on conformational energy calcns. on
disubstituted glycine derivs. AcNHCR2CONHMe (R = Et, Pr, Ph, CH2Ph)
and solid-state conformations of their corresponding peptide derivs. by xray crystallog.
15.
Structural characterization of the β -bend ribbon spiral: Crystallographic
analysis of two long (L-Pro-Aib)n sequential peptides. Benedetti, E.; Di
Blasio, B.; Pavone, V.; Pedone, C.; Crisma, M.; Anzolin, L.; Toniolo, C.
Editor(s): Smith, John A.; Rivier, Jean E. Pept.: Chem. Biol., Proc. Am.
Pept. Symp., 12th (1992), Meeting Date 1991, 290-1. Publisher: ESCOM,
Leiden, Neth.,
Abstract: A report from a symposium on the prepn. of the title compds. 4BrC6H4CO-Aib-(Pro-Aib)n-OMe (I; n = 2-5; Aib = α-aminoisobutyric
acid) and the crystal structure of I (n = 2, 3).
16.
The polypeptide 310-helix. Benedetti, Ettore; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo; Santini, Antonello; Toniolo, Claudio; Crisma,
Marco;
Formaggio,
Fernando;
Sartore,
Luciana.
Editor(s):
Renugoplakrishnan, Venkatesan. Proteins (1991), 302-4. Publisher: ESCOM,
Leiden, Neth.,
Abstract: A report from a symposium on the relative stabilities of 310- and αhelicies of α-aminoisobutyric acid (Aib) residues in the solid state by anal.
of crystal structures of 3 (Aib)n (n = 6, 8, 10) homooligopeptides and 3 (AibL-Ala)m (m = 3-5) sequential oligopeptides.
17.
Helical structures in peptides. Benedetti, Ettore; Di Blasio, Benedetto;
Pavone, Vincenzo; Pedone, Carlo. Editor(s): Giralt, Ernest; Andreu, David.
Pept. 1990, Proc. Eur. Pept. Symp., 21st (1991), Meeting Date 1990, 454-5.
Publisher: ESCOM Sci. Publ., Leiden, Neth.,
Abstract: A report from a symposium on a statistical anal. of 54 independent
helical mols. using highly refined crystal structure detns. A total of 407
residues were taken into account, of which 258 were considered in helical
conformation, being part of at least 4 successive amino acid residues with
ϕ,ψ values pertinent to either the α or the 310 helix. The min. peptide length
required for onset of α-helixes is 7 residues.
18.
β-Ala residues for molecular design of cyclic peptides containing
112
hydrogen-bonding turns. Di Blasio, B.; Pavone, V.; Yang, X.; Lombardi, A.;
Benedetti, E.; Pedone, C. Editor(s): Rivier, Jean E.; Marshall, Garland R.
Pept.: Chem., Struct. Biol., Proc. Am. Pept. Symp., 11th (1990), Meeting
Date 1989, 667-8. Publisher: ESCOM Sci. Pub., Leiden, Neth.,
Abstract: A report from a symposium on the prepn. and structures of βalanine-contg. cyclic peptides cyclo-[(Pro)n-Phe-βAla-βAla] (n = 1, 2).
19.
Symmetry in synthetic and natural peptides. Benedetti, E.; Di Blasio, B.;
Lombardi, A.; Pavone, V.; Pedone, C. Editor(s): Gruber, Bruno; Yopp, John
H. Symmetries Sci. 4 [Proc. Symp.] (1990), Meeting Date 1989, 1-14.
Publisher: Plenum, New York, N. Y.,
Abstract: A review with 38 refs. on the symmetry and conformations of
cyclic peptides, linear peptides, and helical structures
20.
Reactivity and structure of platinum(II) complexes in peptide synthesis.
Lombardi, A.; Pavone, V.; Pedone, C.; Di Blasio, B.; Benedetti, E. Colloque
INSERM (1989), 174(Forum Pept., 2nd, 1988), 207-10.
Abstract: A report from a forum on peptides. Pt amino acid complexes, e.g.
trans-[Cl2PtL2] (L = alanine, valine, α-aminoisobutyric acid), were prepd.
The reactivity of the Pt complexes in peptide synthesis was studied.
21.
Cyclic regularly alternating L,D peptides. Pavone, V.; Benedetti, E.; Di
Blasio, B.; Pedone, C.; Lombardi, A.; Lorenzi, G. P. Editor(s): Jung,
Guenther; Bayer, Ernst. Pept., Proc. Eur. Pept. Symp., 20th (1989), Meeting
Date 1988, 447-9. Publisher: de Gruyter, Berlin, Fed. Rep. Ger.,
Abstract: A symposium report on the crystal structure and conformation of
title peptides cyclo(L-Val-D-Val)3 and cyclo(L-Phe-D-Phe)3.
22.
Metal ion binding peptides: solid-state conformation of cyclo(Glu-Leu-ProGly-Lys-Leu-Pro-Gly)cyclo(1γ-5ε)Gly. Di Blasio, B.; Pavone, V.; Pedone,
C.; Benedetti, E.; Spiniello, O.; Zanotti, G.; Blout, E. R. Editor(s): Jung,
Abstract: A symposium report on the crystal structure and solid-state
conformation of the title homodetic bicyclic nonapeptide.
23.
Crystal-state 310-α -helix conformational transition induced by peptide chain
lengthening. Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini,
113
A.; Bavoso, A.; Toniolo, C.; Crisma, M.; Sartore, L. Editor(s): Jung,
Abstract: A symposium report on the detn. of the solid-state conformation
of p-BrC6H4CO-(Aib-Ala)n-OMe (Aib - NHCMe2CO; n = 4, 5, 6) by xray diffraction anal. All peptides in the solid state have a helical structure
stabilized by NH...OC H bonds. In all peptides the central core of the helix
is always of the α-helical type with the formation of consecutive intramol.
H-bonded C13 ring structures. At both terminal ends in all peptides, C10
ring structures are obsd.
24.
Crystal and molecular structure of S-deoxo [γ (R) hydroxy-Ile3]amaninamide: a synthetic analog of Amanita toxins. Zanotti, Giancarlo;
Wieland, Theodor; Benedetti, Ettore; Di Blasio, Benedetto; Pavone,
Vincenzo; Pedone, Carlo. Editor(s): Marshall, Garland R. Pept.: Chem.
Biol., Proc. Am. Pept. Symp. 10th (1988), Meeting Date 1987, 93-4. Publisher:
ESCOM Sci. Pub., Leiden, Neth.,
Abstract: A symposium on the crystal structure of the title compd.
25.
Structural versatility of peptides from Cα,α-dialkylated glycines: ACC3rich peptides. Toniolo, Claudio; Crisma, Marco; Valle, Giovanni; Bonora,
Gian Maria; Barone, Vincenzo; Benedetti, Ettore; Di Blasio, Benedetto;
Pavone, Vincenzo; Pedone, Carlo; et al. Peptide Chemistry (1988), Volume
Date 1987, 45-8.
Abstract: A report on the structure of 1-aminocyclopropane-1-carboxylic acid
(Acc3)-rich peptides. Crystal and mol. structures and conformational
energy calcns. are discussed.
26.
Structural versatility of peptides from Cα,α-dialkylated glycines: Acc5- and
Acc6-containing peptides. Benedetti, E.; Barone, V.; Bavoso, A.; Di Blasio,
B.; Lelj, F.; Pavone, V.; Pedone, C.; Toniolo, C.; Crisma, M.; Bonora, G. M.
Editor(s): Theodoropoulos, Dimitrios. Pept., Proc. Eur. Pept. Symp., 19th
(1987), Meeting Date 1986, 315-18. Publisher: de Gruyter, Berlin, Fed. Rep.
Ger.,
Abstract: A symposium on conformational energy calcns., x-ray diffraction
anal., and IR and 1H NMR spectra of the title peptides (Acc5 = αaminopentanecarboxylic acid, Acc6 = α-aminocyclohexanecarboxylic acid).
27.
Thiolation and epimerization of α-hydroxy α-amino acid derivatives by
114
the Mitsunobu reaction. Nagai, Ukon; Kato, Rika; Pavone, Vincenzo.
Peptide Chemistry (1988), Volume Date 1987, 187-90.
Abstract: A report on the thiolation and epimerization of α-hydroxy αamino acid derivs. by the Mitsunobu reaction.
28.
Folded, helical and extended structures of peptides from Cα ,α -dialkylated
α -amino acids. Solid-state and solution conformation of homopeptides
from Cα ,α -diethylglycine. Bavoso, Alfonso; Benedetti, Ettore; Di Blasio,
Benedetto; Pavone, Vincenzo; Pedone, Carlo; Toniolo, Claudio; Bonora,
Gian Maria; Leplawy, Miroslaw T.; Redlinski, Adam; Kaczmarek,
Krzysztof. D. Pept.: Struct. Funct., Proc. Am. Pept. Symp., 9th (1985), 193-6.
Abstract: Structure of diethylglycine (Deg) homopeptides were detd. by (1)
conformational energy calcns. for Ac-Deg-NHMe, (2) diffraction anal. of
CF3CO-(Deg)n-OCMe3 (I; n = 3-5), and (3) IR and 1H NMR of I (n = 2-5).
The intramol. H bonded C5 structures found were remarkably stable to
diln., heating, and addn. of polar solvent.
29.
Folded and extended structures of homo-peptides from α ,α -dialkylated α amino acids. Benedetti, Ettore; Barone, V.; Bavoso, A.; Di Blasio, B.;
Grimaldi, P.; Lely, F.; Pavone, V.; Pedone, C.; Bonora, G. M.; et al.
Editor(s): Ragnarsson, Ulf. Pept., Proc. Eur. Pept. Symp., 18th (1984), 603-6.
Publisher: Almqvist & Wiksell, Stockholm, Swed.,
Abstract: Conformational preferences of α,α-dipropylglycine (Dpg) and αmethyl-α-ethylglycine derivs. and homopeptides were compared with those
of the α,α-dimethylglycine and α-aminoisobutyric acid (Aib) series. The IR
and 1H NMR results in CDCl3 soln. indicate that the Aib peptides assume a
310-helix conformation and the Dpg peptides assume a multiple-C5
conformation.
30.
Membrane-active peptaibol antibiotics: conformational preferences of the 29 segment of emerimicins III and IV and all related short sequences.
Toniolo, Claudio; Bonora, Gian Maria; Mapelli, Claudio; Benedetti, Ettore;
Bavoso, Alfonso; Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo.
Editor(s): Hruby, Victor J.; Rich, Daniel H. Pept.: Struct. Funct., Proc. Am.
Pept. Symp., 8th (1983), 495-8. Publisher: Pierce Chem. Co., Rockford, Ill,
Abstract: IR and CD spectra of Z-(Aib)3-Val-Gly-Leu-(Aib)2-OMe (Aib =
α-aminoisobutyric acid residue)(I) and of several fragments in soln.
indicated that I assumes a right-handed α-helical conformation.
115
31.
Channel-forming molecules: conformation of peptides with alternating L
and D residues as models of gramicidin A. Pedone, Carlo; Barone,
Vincenzo; Benedetti, Ettore; Di Blasio, Benedetto; Esposito, Gennaro;
Garolla, Francesco Lelj; Pavone, Vincenzo; Lorenzi, Gian Paolo. Editor(s):
Hruby, Victor J.; Rich, Daniel H. Pept.: Struct. Funct., Proc. Am. Pept.
Symp., 8th (1983), 473-6. Publisher: Pierce Chem. Co., Rockford, Ill,
Abstract: Semiempirical calcns. of the conformations of peptides contg.
alternating D and L amino acids were performed, and the results compared
with the results of x-ray crystallog. data. The contributions of electrostatic
and nonbonded interactions to the conformational stability of these peptides
are discussed.
32.
Conformational features of alternating L,D peptides. Bavoso, Alfonso;
Barone, Vincenzo; Esposito, Gennaro; Lelj, Francesco; Lorenzi, Gian Paolo.
Editor(s): Blaha, Karel; Malon, Petr. Pept., Proc. Eur. Pept. Symp., 17th
(1983), Meeting Date 1982, 699-704. Publisher: de Gruyter, Berlin, Fed. Rep.
Ger.,
Abstract: The conformations of Boc-D-Leu-L-Leu-OMe (I, Boc =
Me3CO2C), Boc-L-Ile-D-aIle-OMe (II), Boc-(D-aIle-L-Ile)3-OMe (III),
Boc-(L-Val-D-Val)4-OMe (IV), and Boc-(D-Phe-L-Phe)4-OMe were
studied by crystallog. data and theor. calcns. I and II present an V-shaped
structure with ϕ and ψ torsion angles falling in the calcd. min. energy
regions. III adopts a folded shape due to the formation of a type II β-turn
fused with an α-turn in which both are included in a C17-membered
intramol. H-bonded ring structure. The crystal structure of IV indicated
double-stranded β-helical dimers with antiparallel chains.
33.
Peptaibol antibiotics: a study on the helical structure of emerimicins.
Toniolo, Claudio; Bonora, Gian Maria; Benedetti, Ettore; Bavoso, Alfonso;
Di Blasio, Benedetto; Pavone, Vincenzo; Pedone, Carlo. Editor(s): Blaha,
Karel; Malon, Petr. Pept., Proc. Eur. Pept. Symp., 17th (1983), Meeting Date
1982, 741-4. Publisher: de Gruyter, Berlin, Fed. Rep. Ger.,
Abstract: The conformational preferences in soln. of the protected 2-9
segment of emerimicins III and IV, and several related short sequences,
were studied by IR and CD spectroscopies. The structural preferences of Z(Aib)3-OCMe3 (Z = PhCH2O2C, Aib = α-aminoisobutyric acid residue) (I)
and Z-(Aib)3-L-Val-X-OMe [X = bond (II) or Gly (III)] were confirmed
by x-ray diffraction anal. The structures of I, II, and III are characterized by
116
C10-conformations [one type-III (or type III'), a double type-III', and triple,
resp.].
117

curriculum vitae prof. vincenzo pavone

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