Journal
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
Volume 20, Issue -, Pages 4667-4687Publisher
ELSEVIER
DOI: 10.1016/j.csbj.2022.08.046
Keywords
Cathepsin V; Small-Molecule Inhibitors; Antitumor therapy; Cancer; Cystatin F
Funding
- Slovenian Research Agency
- [J4-1776]
- [P4-0127]
- [J3-3071]
- [J3-2516]
- [P1-0208]
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A new potent inhibitor of cathepsin V has been identified, which significantly affects cell proliferation, elastin degradation, and immune cell cytotoxicity, suggesting its potential application in cancer therapy.
Cathepsin V is a human lysosomal cysteine peptidase with specific functions during pathological pro-cesses 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 Vis a potential target for new approaches to cancer therapy. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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