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Titolo:
DEVELOPMENT OF THE FIRST POTENT AND SELECTIVE INHIBITOR OF THE ZINC ENDOPEPTIDASE NEUROLYSIN USING A SYSTEMATIC-APPROACH BASED ON COMBINATORIAL CHEMISTRY OF PHOSPHINIC PEPTIDES
Autore:
JIRACEK J; YIOTAKIS A; VINCENT B; CHECLER F; DIVE V;
Indirizzi:
CENS,CEA,DEPT INGN & ETUD PROT,DSV F-91191 GIF SUR YVETTE FRANCE CENS,CEA,DEPT INGN & ETUD PROT,DSV F-91191 GIF SUR YVETTE FRANCE UNIV ATHENS,ORGAN CHEM LAB,DEPT ORGAN CHEM ZOGRAFOS 15771 ATHENS GREECE UNIV NICE,INST PHARMACOL MOL & CELLULAIRE F-06560 VALBONNE FRANCE
Titolo Testata:
The Journal of biological chemistry
fascicolo: 32, volume: 271, anno: 1996,
pagine: 19606 - 19611
SICI:
0021-9258(1996)271:32<19606:DOTFPA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
BINDING ENZYME-INHIBITORS; PZ-PEPTIDASE; RAT-BRAIN; MICROSOMAL ENDOPEPTIDASE; PROCESSING PROPROTEINS; BACTERIAL COLLAGENASE; SUBSTRATE-SPECIFICITY; MOLECULAR-CLONING; SLOW-BINDING; PURIFICATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
36
Recensione:
Indirizzi per estratti:
Citazione:
J. Jiracek et al., "DEVELOPMENT OF THE FIRST POTENT AND SELECTIVE INHIBITOR OF THE ZINC ENDOPEPTIDASE NEUROLYSIN USING A SYSTEMATIC-APPROACH BASED ON COMBINATORIAL CHEMISTRY OF PHOSPHINIC PEPTIDES", The Journal of biological chemistry, 271(32), 1996, pp. 19606-19611

Abstract

A mew systematic approach, based on combinatorial chemistry of phosphinic peptides, is proposed for rapid development of highly potent and selective inhibitors of zinc metalloproteases. This strategy first evaluates the effects on the inhibitory potency and selectivity of the following parameters: 1) size of the phosphinic peptides, 2) position ofthe phosphinic bond in the sequence, and 3) the state (free or blocked) of the peptide extremities. After this selection step, the influence of the inhibitor sequence is analyzed in order to determine the identity of the residues that optimized both the potency and the selectivity, We demonstrate the efficiency of this novel approach in rapid identification of the first potent inhibitor of the mammalian zinc endopeptidase neurolysin (24-16), able to discriminate between this enzyme and the related zinc endopeptidase thimet oligopeptidase (24-15). The most potent and selective inhibitor developed in this study, Pro-LPhe Psi(PO2CH2)Gly-Pro, displays a K-i value of 4 nM for 24-16 and is 2000 times less potent on 24-15. The specific recognition of such a free phosphinic tetrapeptide by 24-16, as well as the unique specificity of the 24-16 S-2 and S-2' subsites for proline, unveiled by this study, arediscussed ill terms of their possible significance for the function of this enzyme and its related zinc endopeptidase activities.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/04/20 alle ore 02:04:27