2. Academic Validation
  3. Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain

Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain

  • ACS Med Chem Lett. 2024 Dec 23;16(1):72-79. doi: 10.1021/acsmedchemlett.4c00460.
Juan Pablo Cerutti 1 2,  Lucas Abreu Diniz 3,  Viviane Corrêa Santos 3 4,  Salomé Catalina Vilchez Larrea 5,  Guillermo Daniel Alonso 5,  Rafaela Salgado Ferreira 3,  Mario Alfredo Quevedo 1,  Wim Dehaen 2
Affiliations

Affiliations

  • 1 Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC), Córdoba 5000, Argentina.
  • 2 Sustainable Chemistry for Metals and Molecules, Department of Chemistry, KU Leuven, Leuven 3000, Belgium.
  • 3 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
  • 4 Department of Chemistry, Grand Valley State University, 1 Campus Drive, Allendale, Michigan 49401, United States.
  • 5 Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Buenos Aires 1428, Argentina.
PMID: 39811116 DOI: 10.1021/acsmedchemlett.4c00460
Abstract

Cruzipain (CZP) is an essential cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease, and a promising druggable target. To date, no CZP inhibitors have reached clinical use, with research efforts mostly hampered by insufficient potency, limited target selectivity or lack of bioactivity translation from the isolated Enzyme to the Parasite in cellular environments. In this study, we report the design of SH-1, a 1,2,3-triazole-based targeted covalent inhibitor with nanomolar potency (IC50 = 28 nM) and null inhibition of human Cathepsin L. SH-1 demonstrates bioactivity translation comparable to that of K777 (1-10 μM), a CZP inhibitor previously advanced to clinical trials. Experimental findings indicate that SH-1 forms a reversible covalent bond with Cys25 in CZP, while in silico and structure-activity relationship studies suggest that this interaction is guided by acid-base equilibrium dynamics. The potential of SH-1 for preclinical development is discussed alongside detailed structure-activity relationships for the further optimization of CZP inhibitors.

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