title: Development of the first potent and selective inhibitor of the zinc endopeptidase neurolysin using a systematic approach based on combinatorial chemistry of phosphinic peptides.
abstract: A new 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 of the 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-LPhePsi(PO2CH2)Gly-Pro, displays a Ki 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 S2 and S2' subsites for proline, unveiled by this study, are discussed in terms of their possible significance for the function of this enzyme and its related zinc endopeptidase activities.
authors.affiliation: Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines, DSV, CE-Saclay 91191 Gif-sur-Yvette Cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Jirácek
authors.forename: A
authors.initials: A
authors.lastname: Yiotakis
authors.forename: B
authors.initials: B
authors.lastname: Vincent
authors.forename: F
authors.initials: F
authors.lastname: Checler
authors.forename: V
authors.initials: V
authors.lastname: Dive
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010721:Phosphinic Acids / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
chemical_list: D009842:Oligopeptides; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; C062316:neurolysin