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  • Structural elucidation and antiviral activity of covalent cathepsin L inhibitors [Elektronski vir]
    Falke, Sven ...
    Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, ... cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess antiviral activity in the very low nanomolar EC50 range in Vero E6 cells and inhibit CatL in the picomolar Ki range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease α-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 Å present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development.
    Vir: Journal of medicinal chemistry [Elektronski vir]. - ISSN 1520-4804 (Vol. 67, iss. 9, May 2024, str. 7048-7067)
    Vrsta gradiva - e-članek ; neleposlovje za odrasle
    Leto - 2024
    Jezik - angleški
    COBISS.SI-ID - 197982979

    Povezava(-e):

    https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02351
    DOI

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