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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor

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Author(s):
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Ribeiro, Jean F. R. [1] ; Cianni, Lorenzo [1] ; Li, Chan [2] ; Warwick, Thomas G. [2] ; de Vita, Daniela [1] ; Rosini, Fabiana [1] ; Rocho, Fernanda dos Reis [1] ; Martins, Felipe C. P. [1] ; Kenny, Peter W. [1] ; Lameira, Jeronimo [1, 3] ; Leitao, Andrei [1] ; Emsley, Jonas [2] ; Montanari, Carlos A. [1]
Total Authors: 13
Affiliation:
[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp, Sao Carlos - Brazil
[2] Univ Nottingham, Ctr Biomol Sci, Sch Pharm, Nottingham - England
[3] Fed Univ Para, Lab Design & Dev Pharmaceut, Belem, Para - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 28, n. 22 NOV 15 2020.
Web of Science Citations: 0
Abstract

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 angstrom X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases. (AU)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Projects - Thematic Grants