Cerutti Juan Pablo, Diniz Lucas Abreu, Corrêa Santos Viviane, Vilchez Larrea Salomé Catalina, Alonso Guillermo Daniel, Ferreira Rafaela Salgado, Dehaen Wim, Quevedo Mario Alfredo
Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (FCQ-UNC), Córdoba 5000, Argentina.
Sustainable Chemistry for Metals and Molecules, Department of Chemistry, KU Leuven, Leuven 3000, Belgium.
ACS Med Chem Lett. 2025 Feb 24;16(3):464-474. doi: 10.1021/acsmedchemlett.4c00631. eCollection 2025 Mar 13.
Chagas disease remains a neglected tropical disease with limited therapeutic options and a pressing need for new antichagasic agents. In this context, Cruzipain (CZP), the main cysteine protease of , has been validated as a promising target for reversible targeted covalent inhibitors (TCIs). Building upon our previous research, this study reports phenyl thiosulfonate (TSO)-based TCIs, designed to optimize enzymatic performance and enhance bioactivity translation from CZP inhibition to -infected cell models. Among ten potent phenyl TSO TCIs, exhibited high CZP inhibitory potency, selectivity over human cathepsin L, and excellent bioactivity translation in parasite-infected cells. Computational studies highlighted the dual benefit of the TSO moiety in combining optimal reactivity with enhanced encounter complexes' stability. Overall, these findings position triazole-based phenyl TSO derivatives as promising candidates for rational CZP inhibitor design, representing a valuable contribution for developing innovative antichagasic agents.
恰加斯病仍然是一种被忽视的热带病，治疗选择有限，迫切需要新的抗锥虫病药物。在此背景下，克鲁斯蛋白酶（CZP）作为克氏锥虫的主要半胱氨酸蛋白酶，已被确认为可逆靶向共价抑制剂（TCIs）的一个有前景的靶点。基于我们之前的研究，本研究报告了基于苯硫代磺酸盐（TSO）的TCIs，其设计目的是优化酶活性，并增强从抑制CZP到感染锥虫的细胞模型的生物活性转化。在十种有效的苯TSO TCIs中，表现出高CZP抑制效力、对人组织蛋白酶L的选择性，以及在寄生虫感染细胞中的优异生物活性转化。计算研究突出了TSO部分在将最佳反应性与增强的相遇复合物稳定性相结合方面的双重益处。总体而言，这些发现将基于三唑的苯TSO衍生物定位为合理设计CZP抑制剂的有前景的候选物，为开发创新的抗锥虫病药物做出了有价值的贡献。
