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Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L
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SYSNO ASEP 0558333 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L Author(s) Ashhurst, A. S. (AU)
Tang, A. H. (AU)
Fajtová, Pavla (UOCHB-X) RID, ORCID
Yoon, M. C. (US)
Aggarwal, A. (AU)
Bedding, M. J. (AU)
Stoye, A. (AU)
Beretta, L. (US)
Pwee, D. (US)
Drelich, A. (US)
Skinner, D. (US)
Li, L. (US)
Meek, T. D. (US)
McKerrow, J. H. (US)
Hook, V. (US)
Tseng, C. T. (US)
Larance, M. (AU)
Turville, S. (AU)
Gerwick, W. H. (US)
O'Donoghue, A. J. (US)
Payne, R. J. (AU)Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 65, č. 4 (2022), s. 2956-2970Number of pages 15 s. Language eng - English Country US - United States Keywords acute respiratory syndrome ; cell entry ; selective inhibitor OECD category Biochemistry and molecular biology Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000797940600016 EID SCOPUS 85119036179 DOI 10.1021/acs.jmedchem.1c01494 Annotation Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2), however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2023 Electronic address https://doi.org/10.1021/acs.jmedchem.1c01494
Number of the records: 1