Medicinal Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, São Paulo, Brazil.
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
PLoS Negl Trop Dis. 2020 Mar 12;14(3):e0007755. doi: 10.1371/journal.pntd.0007755. eCollection 2020 Mar.
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
半胱氨酸蛋白酶 cruzipain 被认为是治疗恰加斯病治疗干预的有效靶点。设计、合成了一系列 26 种新化合物，并对重组 cruzain（Cz）进行了测试，以绘制其 S1/S1'亚基。该系列还对四种人类半胱氨酸蛋白酶（CatB、CatK、CatL、CatS）和 Leishmania mexicana CPB 进行了评估，CPB 是治疗皮肤利什曼病的潜在靶点。合成的化合物是基于 P1（十个）、P2（六个）和 P3（四个不同的构建块）中不同部分的最有前途的组合设计的二肽腈。有 8 种化合物对 Cz 的 Ki 值小于 20.0 nM，而有 3 种化合物对 LmCPB 的 Ki 值小于 20.0 nM。三种抑制剂的 EC50 值约为 4.0 μM，根据抗锥虫作用与苯并咪唑相当。我们的定位方法和相应的构效关系为治疗相关半胱氨酸蛋白酶的特定配体-靶相互作用提供了深入了解。
