New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović, Ana (avtor), Senjor, Emanuela (avtor), Jukič, Marko (avtor), Bolčina, Lara (avtor), Prunk, Mateja (avtor), Proj, Matic (avtor), Perišić, Milica (avtor), Gobec, Stanislav (avtor), Kos, Janko (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: cathepsin V, small-molecule inhibitors, antitumor therapy, cancer, cystatin F
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: Str. 4667-4687
• Številčenje: Vol. 20
• PID: 20.500.12556/RUL-143720
• UDK: 577
• ISSN pri članku: 2001-0370
• DOI: 10.1016/j.csbj.2022.08.046
• COBISS.SI-ID: 119687939
• Datum objave v RUL: 15.03.2023

Gradivo je del revije

• Naslov: Computational and structural biotechnology journal
• Založnik: Elsevier, Research Network of Computational and Structural Biotechnology
• ISSN: 2001-0370
• COBISS.SI-ID: 5068826

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.