Počet záznamů: 1  

General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases

  1. 1.
    0484652 - ÚOCHB 2018 RIV US eng J - Článek v odborném periodiku
    Tichá, Anežka - Stanchev, Stancho - Vinothkumar, K. R. - Mikles, David C. - Pachl, Petr - Began, Jakub - Škerle, Jan - Švehlová, Kateřina - Nguyen, M. T. N. - Verhelst, S. H. L. - Johnson, D. C. - Bachovchin, D. A. - Lepšík, Martin - Majer, Pavel - Stříšovský, Kvido
    General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases.
    Cell Chemical Biology. Roč. 24, č. 12 (2017), s. 1523-1536. ISSN 2451-9448. E-ISSN 2451-9448
    Grant CEP: GA MŠk(CZ) LK11206; GA MŠk LO1302; GA MŠk(CZ) LO1304; GA ČR(CZ) GBP208/12/G016
    GRANT EU: European Commission(XE) 304154 - Rhomboid substrates
    Grant ostatní: EMBO(DE) 2329
    Institucionální podpora: RVO:61388963
    Klíčová slova: alpha-ketoamide inhibitors * activity-based probes * intramembrane protease
    Obor OECD: Biochemistry and molecular biology
    Impakt faktor: 5.592, rok: 2017
    http://www.sciencedirect.com/science/article/pii/S2451945617303513?via%3Dihub

    Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl alpha-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a sub-strate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.
    Trvalý link: http://hdl.handle.net/11104/0279803


    Vědecká data: CSB Protein Data Bank, CSB Protein Data Bank, CSB Protein Data Bank, CSB Protein Data Bank
     
     
Počet záznamů: 1