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 hig...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022003804 |
| _version_ | 1797978146205597696 |
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| author | Ana Mitrović Emanuela Senjor Marko Jukić Lara Bolčina Mateja Prunk Matic Proj Milica Perišić Nanut Stanislav Gobec Janko Kos |
| author_facet | Ana Mitrović Emanuela Senjor Marko Jukić Lara Bolčina Mateja Prunk Matic Proj Milica Perišić Nanut Stanislav Gobec Janko Kos |
| author_sort | Ana Mitrović |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:19:25Z |
| format | Article |
| id | doaj.art-4a44fe59f8b842328973cf7efc4be90a |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:19:25Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-4a44fe59f8b842328973cf7efc4be90a2022-12-24T04:54:07ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012046674687New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicityAna Mitrović0Emanuela Senjor1Marko Jukić2Lara Bolčina3Mateja Prunk4Matic Proj5Milica Perišić Nanut6Stanislav Gobec7Janko Kos8Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia; Corresponding author at: Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, SloveniaCathepsin 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.http://www.sciencedirect.com/science/article/pii/S2001037022003804Cathepsin VSmall-Molecule InhibitorsAntitumor therapyCancerCystatin F |
| spellingShingle | Ana Mitrović Emanuela Senjor Marko Jukić Lara Bolčina Mateja Prunk Matic Proj Milica Perišić Nanut Stanislav Gobec Janko Kos New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity Computational and Structural Biotechnology Journal Cathepsin V Small-Molecule Inhibitors Antitumor therapy Cancer Cystatin F |
| title | New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| title_full | New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| title_fullStr | New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| title_full_unstemmed | New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| title_short | New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| title_sort | new inhibitors of cathepsin v impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity |
| topic | Cathepsin V Small-Molecule Inhibitors Antitumor therapy Cancer Cystatin F |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022003804 |
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