Mitrović Ana, Senjor Emanuela, Jukić Marko, Bolčina Lara, Prunk Mateja, Proj Matic, Nanut Milica Perišić, Gobec Stanislav, Kos Janko
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Comput Struct Biotechnol J. 2022 Aug 28;20:4667-4687. doi: 10.1016/j.csbj.2022.08.046. eCollection 2022.
Cathepsin V is a human lysosomal cysteine peptidase with specific functions during pathological processes and is as such a promising therapeutic target. Peptidase inhibitors represent powerful pharmacological tools for regulating excessive proteolytic activity in various diseases. Cathepsin V is highly related to cathepsin L but differs in tissue distribution, binding site morphology, substrate specificity, and function. To validate its therapeutic potential and extend the number of potent and selective cathepsin V inhibitors, we used virtual high-throughput screening of commercially available compound libraries followed by an evaluation of kinetic properties to identify novel potent and selective cathepsin V inhibitors. We identified the ureido methylpiperidine carboxylate derivative, compound , as a reversible, selective, and potent inhibitor of cathepsin V. It also exhibited the most preferable characteristics for further evaluation with functional assays that simulate the processes in which cathepsin V is known to play an important role. Compound exerted significant effects on cell proliferation, elastin degradation, and immune cell cytotoxicity. The latter was increased because compound impaired conversion of immunosuppressive factor cystatin F to its active monomeric form. Taken together, our results present novel potent inhibitors of cathepsin V and provide new hit compounds for detailed development and optimization. Further, we demonstrate that cathepsin V is a potential target for new approaches to cancer therapy.
组织蛋白酶V是一种人类溶酶体半胱氨酸肽酶，在病理过程中具有特定功能，因此是一个有前景的治疗靶点。肽酶抑制剂是调节各种疾病中过度蛋白水解活性的有力药理学工具。组织蛋白酶V与组织蛋白酶L高度相关，但在组织分布、结合位点形态、底物特异性和功能方面存在差异。为了验证其治疗潜力并增加强效和选择性组织蛋白酶V抑制剂的数量，我们对市售化合物库进行了虚拟高通量筛选，随后评估动力学性质以鉴定新型强效和选择性组织蛋白酶V抑制剂。我们鉴定出脲基甲基哌啶羧酸盐衍生物化合物 作为组织蛋白酶V的可逆、选择性和强效抑制剂。它还表现出最适合通过模拟已知组织蛋白酶V起重要作用的过程的功能测定进行进一步评估的特性。化合物 对细胞增殖、弹性蛋白降解和免疫细胞细胞毒性产生显著影响。后者增加是因为化合物 损害了免疫抑制因子胱抑素F向其活性单体形式的转化。综上所述，我们的结果展示了新型强效组织蛋白酶V抑制剂，并为详细的开发和优化提供了新的命中化合物。此外，我们证明组织蛋白酶V是癌症治疗新方法的潜在靶点。
