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New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity
ID Mitrović, Ana (Avtor), ID Senjor, Emanuela (Avtor), ID Jukič, Marko (Avtor), ID Bolčina, Lara (Avtor), ID Prunk, Mateja (Avtor), ID Proj, Matic (Avtor), ID Perišić, Milica (Avtor), ID Gobec, Stanislav (Avtor), ID Kos, Janko (Avtor)

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URLURL - Izvorni URL, za dostop obiščite https://www.sciencedirect.com/science/article/pii/S2001037022003804 Povezava se odpre v novem oknu

Izvleček
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 Povezava se odpre v novem oknu
UDK:577
ISSN pri članku:2001-0370
DOI:10.1016/j.csbj.2022.08.046 Povezava se odpre v novem oknu
COBISS.SI-ID:119687939 Povezava se odpre v novem oknu
Datum objave v RUL:15.03.2023
Število ogledov:271
Število prenosov:30
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
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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 Povezava se odpre v novem oknu

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.

Projekti

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J4-1776-2019
Naslov:Izboljšanje imunoterapevtske vrednosti NK celic z modulacijo cistatina F

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:P4-0127-2019
Naslov:Farmacevtska biotehnologija: znanost za zdravje

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J3-3071-2021
Naslov:Katepsina B in X v tumorskih matičnih celicah raka dojke – molekulske tarče in pomen za protitumorno terapijo

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J3-2516-2020
Naslov:Cistatin F kot mediator imunske supresije v mikrookolju glioblastoma

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:P1-0208-2015
Naslov:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

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