Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Carlos, Brazil.
School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
Bioorg Med Chem. 2020 Nov 15;28(22):115743. doi: 10.1016/j.bmc.2020.115743. Epub 2020 Sep 6.
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.
墨西哥利什曼原虫是一种专性细胞内原生动物寄生虫，可引起影响南美洲和墨西哥的皮肤利什曼病。半胱氨酸蛋白酶 LmCPB 对寄生虫的毒力至关重要，因此，它是抗寄生虫治疗的一个有吸引力的靶点。对基于腈的半胱氨酸蛋白酶抑制剂文库进行了筛选，以开发治疗皮肤利什曼病的方法。几种化合物对 LmCPB 具有足够高的亲和力，可作为药物发现项目的起点，并作为靶标验证的探针。该酶与一个氮杂二肽腈配体共价结合的复合物的 1.4 Å X 射线晶体结构，是第一个被报道的 LmCPB 结构。该结构确定了 LmCPB 抑制的结构-活性关系的映射，揭示了两对结构转化的超加性效应。因此，这项工作增进了我们对基于 LmCPB 结构的抑制剂设计的氮杂二肽和二肽腈结构-活性关系的理解。我们还在相关的半胱氨酸蛋白酶组织蛋白酶 L 和克氏锥虫 cruzain 上测试了同一系列抑制剂。对这些哺乳动物和原生动物蛋白酶的调节代表了针对木瓜蛋白酶样半胱氨酸蛋白酶的新框架。
