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.
Show 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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