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

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 IC 50 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 EC 50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.

• Authors: Anneliese S Ashhurst, Arthur H Tang, Pavla Fajtová, Michael Yoon, Anupriya Aggarwal, Alexander Stoye, Mark Larance, Laura Beretta, Aleksandra Drelich, Danielle Skinner, Linfeng Li, Thomas D Meek, James H McKerrow, Vivian Hook, Chien-Te K Tseng, Stuart Turville, William H Gerwick, Anthony J O'Donoghue, Richard J Payne
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Dec 24 2020) United States
• PMID: 33398273 (Publication Type: Preprint)