PDF(Pubmed)
Abstract：
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 7, as a reversible, selective, and potent inhibitor of cathepsin V. It also exhibited the most preferable characteristics for further evaluation with in vitro functional assays that simulate the processes in which cathepsin V is known to play an important role. Compound 7 exerted significant effects on cell proliferation, elastin degradation, and immune cell cytotoxicity. The latter was increased because compound 7 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.
摘要：
组织蛋白酶V是一种在病理过程中具有特定功能的人溶酶体半胱氨酸肽酶，并且是如此有希望的治疗靶标。肽酶抑制剂代表了在各种疾病中调节过度蛋白水解活性的强大药理学工具。组织蛋白酶V与组织蛋白酶L高度相关，但组织分布不同，结合位点形态学，底物特异性，和功能。为了验证其治疗潜力并扩展有效和选择性的组织蛋白酶V抑制剂的数量，我们对市售化合物文库进行了虚拟高通量筛选,然后对动力学特性进行了评估,以鉴定新型有效和选择性的组织蛋白酶V抑制剂.我们鉴定了脲基甲基哌啶羧酸酯衍生物，化合物7，作为可逆的，选择性,和组织蛋白酶V的有效抑制剂。它还表现出最优选的特征，用于体外功能测定的进一步评估，该体外功能测定模拟了已知组织蛋白酶V发挥重要作用的过程。化合物7对细胞增殖有显著影响,弹性蛋白降解，和免疫细胞的细胞毒性。后者增加是因为化合物7损害了免疫抑制因子胱抑素F向其活性单体形式的转化。一起来看,我们的结果提出了组织蛋白酶V的新型有效抑制剂，并为详细开发和优化提供了新的命中化合物。Further,我们证明组织蛋白酶V是癌症治疗新方法的潜在靶点.
