Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain
Cruzipain (CZP) is an essential cysteine protease of <i>Trypanosoma cruzi</i>, 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 <b>SH-1</b>, a 1,2,3-triazole-based targeted covalent inhibitor with nanomolar potency (IC<sub>50</sub> = 28 nM) and null inhibition of human cathepsin L. <b>SH-1</b> demonstrates bioactivity translation comparable to that of K777 (1-10 μM), a CZP inhibitor previously advanced to clinical trials. Experimental findings indicate that <b>SH-1</b> forms a reversible covalent bond with Cys25 in CZP, while <i>in silico</i> and structure-activity relationship studies suggest that this interaction is guided by acid-base equilibrium dynamics. The potential of <b>SH-1</b> for preclinical development is discussed alongside detailed structure-activity relationships for the further optimization of CZP inhibitors.
Authors
- Viviane Corrêa Santos (ORCID: https://orcid.org/0000-0002-4967-1898)
- Lucas Abreu Diniz (ORCID: https://orcid.org/0009-0005-5922-7087)
- G. Alonso (ORCID: https://orcid.org/0000-0001-9386-9431)
- Rafaela Salgado Ferreira (ORCID: https://orcid.org/0000-0003-3324-0601)
- Juan Pablo Cerutti (ORCID: https://orcid.org/0000-0003-2271-5050)
- Wim Dehaen (ORCID: https://orcid.org/0000-0002-9597-0629)
- Mario A. Quevedo (ORCID: https://orcid.org/0000-0002-7891-7834)
- Salomé C. Vilchez Larrea (ORCID: https://orcid.org/0000-0001-8302-1509)
Institutions
- Universidade Federal de Minas Gerais (BR)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Universidad Nacional de Córdoba (AR)
- Université Bourgogne Franche-Comté (FR)
- Experimental Medicine and Biology Institute (AR)
- Grand Valley State University (US)
- KU Leuven (BE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00460
- Citations
- 2
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.77
Funders
- Universidad Nacional de Córdoba
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Ministerio de Ciencia, Tecnología e Innovación Productiva
- Fonds Wetenschappelijk Onderzoek
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais
- Vlaamse regering
- University of California, San Francisco
- Secretaria de Ciencia y Tecnología - Universidad Nacional de Córdoba
- Agencia Nacional de Promoción Científica y Tecnológica