Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

Ashhurst, A.; Tang, A.; Fajtova, P.; Yoon, M.; Aggarwal, A.; Stoye, A.; Larance, M.; Beretta, L.; Drelich, A.; Skinner, D.; Li, L.; Meek, T.; McKerrow, J.; Hook, V.; Tseng, C.-T.; Turville, S. G.; Gerwick, W.; O'Donoghue, A.; Payne, R. J.

doi:10.1101/2020.12.23.424111

bioRxiv · 10.1101/2020.12.23.424111

Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

Ashhurst, A.·Tang, A.·Fajtova, P.·Yoon, M.·Aggarwal, A.·Stoye, A.·Larance, M.·Beretta, L.·Drelich, A.·Skinner, D.·Li, L.·Meek, T.·McKerrow, J.·Hook, V.·Tseng, C.-T.·Turville, S. G.·Gerwick, W.·O'Donoghue, A.·Payne, R. J.

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Abstract

The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.

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Ashhurst, A., Tang, A., Fajtova, P., Yoon, M., Aggarwal, A., Stoye, A., Larance, M., Beretta, L., Drelich, A., Skinner, D., Li, L., Meek, T., McKerrow, J., Hook, V., Tseng, C.-T., Turville, S. G., Gerwick, W., O'Donoghue, A., Payne, R. J.. 2020-12-25. Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L. https://doi.org/10.1101/2020.12.23.424111

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