Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor
| Autor: | Peter W. Kenny, Carlos A. Montanari, Chan Li, Lorenzo Cianni, Andrei Leitão, Fabiana Rosini, Thomas G. Warwick, Daniela De Vita, Felipe Cardoso Prado Martins, Fernanda dos Reis Rocho, Jerônimo Lameira, Jonas Emsley, Jean F. R. Ribeiro |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Proteases
Nitrile Leishmania mexicana Clinical Biochemistry Protozoan Proteins Pharmaceutical Science crystal structure Leishmania mexicana cysteine protease B azadipeptide nitrile inhibitor structure activity relationships (SARs) covalent inhibitor Cysteine Proteinase Inhibitors Molecular Dynamics Simulation Crystallography X-Ray 01 natural sciences Biochemistry Cathepsin B Cathepsin L Structure-Activity Relationship chemistry.chemical_compound Cutaneous leishmaniasis MEDICAMENTO Nitriles parasitic diseases Drug Discovery medicine Trypanosoma cruzi Molecular Biology Aza Compounds Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Dipeptides medicine.disease biology.organism_classification Trypanocidal Agents Cysteine protease 0104 chemical sciences Cysteine Endopeptidases 010404 medicinal & biomolecular chemistry biology.protein Molecular Medicine Cysteine |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | 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 A 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. |
| Databáze: | OpenAIRE |
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