20.500.12556/DiRROS-23485 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. true false true Elsevier Nizozemska Angleški jezik Ni določen © 2022 The Author(s). Neznano 2025-09-04 11:06:41 2025-09-04 11:06:41 2025-10-24 03:54:25 0000-00-00 00:00:00 2022 0 0 str. 4667-4687 Vol. 20 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2022-05-20 2022-08-20 2022-08-28 577 2001-0370 10.1016/j.csbj.2022.08.046 119687939 https://www.sciencedirect.com/science/article/pii/S2001037022003804 1 7a28cdbc-896e-11f0-9bb7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=34734 RAZ_Mitrovic_Ana_2022.pdf RAZ_Mitrovic_Ana_2022.pdf 1 E48CFC3ECF1AA9C72B9F413A8EC5EB96 dcd5aa81a5cd5379b421bc4dae0592fcba18ab845a2636679277b5ef0fcd69e1 f5028cd0-896e-11f0-9bb7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=34735 Institut Jožef Stefan 0 0 0