Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L

0558333 - ÚOCHB 2023 RIV US eng J - Journal Article
Ashhurst, A. S. - Tang, A. H. - Fajtová, Pavla - Yoon, M. C. - Aggarwal, A. - Bedding, M. J. - Stoye, A. - Beretta, L. - Pwee, D. - Drelich, A. - Skinner, D. - Li, L. - Meek, T. D. - McKerrow, J. H. - Hook, V. - Tseng, C. T. - Larance, M. - Turville, S. - Gerwick, W. H. - O'Donoghue, A. J. - Payne, R. J.
Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L.
Journal of Medicinal Chemistry. Roč. 65, č. 4 (2022), s. 2956-2970. ISSN 0022-2623. E-ISSN 1520-4804
Institutional support: RVO:61388963
Keywords : acute respiratory syndrome * cell entry * selective inhibitor
OECD category: Biochemistry and molecular biology
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.1c01494

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.
Permanent Link: http://hdl.handle.net/11104/0332059


Research data: PRIDE