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

  • bioRxiv. 2020 Dec 24;2020.12.23.424111. doi: 10.1101/2020.12.23.424111.
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
PMID: 33398273 DOI: 10.1101/2020.12.23.424111
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.

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