Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes

Giovanni Covaleda, Pablo Gallego, Josep Vendrell, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, Francesc Xavier Aviles, David Reverter, Laurent Devel

Research output: Contribution to journalArticleResearch

2 Citations (Scopus)

Abstract

© 2019 American Chemical Society. Metallocarboxypeptidases (MCPs) of the M14 family are Zn 2+ -dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media.
Original languageEnglish
Pages (from-to)1917-1931
JournalJournal of Medicinal Chemistry
Volume62
DOIs
Publication statusPublished - 28 Feb 2019

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