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

AS. Ashhurst, AH. Tang, P. Fajtová, MC. Yoon, A. Aggarwal, MJ. Bedding, A. Stoye, L. Beretta, D. Pwee, A. Drelich, D. Skinner, L. Li, TD. Meek, JH. McKerrow, V. Hook, CT. Tseng, M. Larance, S. Turville, WH. Gerwick, AJ. O'Donoghue, RJ. Payne

. 2022 ; 65 (4) : 2956-2970. [pub] 20211103

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22010939

Grant support
U01 TW006634 FIC NIH HHS - United States

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.

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