2. Academic Validation
  3. Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor

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

  • Bioorg Med Chem. 2020 Nov 15;28(22):115743. doi: 10.1016/j.bmc.2020.115743.
Jean F R Ribeiro 1,  Lorenzo Cianni 1,  Chan Li 2,  Thomas G Warwick 2,  Daniela de Vita 1,  Fabiana Rosini 1,  Fernanda Dos Reis Rocho 1,  Felipe C P Martins 1,  Peter W Kenny 1,  Jeronimo Lameira 3,  Andrei Leitão 1,  Jonas Emsley 4,  Carlos A Montanari 5
Affiliations

Affiliations

  • 1 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, Brazil.
  • 2 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
  • 3 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, Brazil; Laboratory of Design and Development of Pharmaceuticals, Federal University of Pará, Belém, Brazil.
  • 4 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK. Electronic address: jonas.emsley@nottingham.ac.uk.
  • 5 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, Brazil. Electronic address: Carlos.Montanari@usp.br.
PMID: 33038787 DOI: 10.1016/j.bmc.2020.115743
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 Å 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.

Keywords

Azadipeptide nitrile inhibitor; Covalent inhibitor; Crystal structure; Leishmania mexicana cysteine protease B; Structure activity relationships (SARs).

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