20.500.12556/RUL-143720 New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity 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. cathepsin V small-molecule inhibitors antitumor therapy cancer cystatin F true false true Angleški jezik Neznan jezik Članek v reviji 2023-01-11 03:27:50 2023-03-15 16:36:11 2023-03-16 03:33:02 0000-00-00 00:00:00 2022 0 0 Str. 4667-4687 Vol. 20 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 2001-0370 10.1016/j.csbj.2022.08.046 119687939 New_inhibitors_of_cathepsin_V_impair_tumor_cell_proliferation_and_elastin.pdf New_inhibitors_of_cathepsin_V_impair_tumor_cell_proliferation_and_elastin.pdf 1 CFC1F6AAF50FB2BDB5F6BB879399A2F1 eda8e59e79c8099aa43b4ec9fdba68e69266fb0c682d60355c156559b0a6bef0 3303a9ff-a2e3-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166342 https://www.sciencedirect.com/science/article/pii/S2001037022003804 1 54efa26f-9157-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=165621 Fakulteta za farmacijo 0 0 0