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[Preprint]. 2021 Feb 12:2020.09.12.293498. [Version 3] doi: 10.1101/2020.09.12.293498

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

Britton Boras, Rhys M Jones, Brandon J Anson, Dan Arenson, Lisa Aschenbrenner, Malina A Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E Haupt, Robert Hoffman, Eugene P Kadar, Rob Kania, Emi Kimoto, Melanie G Kirkpatrick, Lorraine Lanyon, Emma K Lendy, Jonathan R Lillis, James Logue, Suman A Luthra, Chunlong Ma, Stephen W Mason, Marisa E McGrath, Stephen Noell, R Scott Obach, Matthew N O’Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F Rogers, Michelle I Rossulek, Jean G Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W Updyke, Stuart Weston, Yuao Zhu, Jun Wang, Arnab K Chatterjee, Andrew D Mesecar, Matthew B Frieman, Annaliesa S Anderson, Charlotte Allerton
PMCID: PMC7491518  PMID: 32935104

Abstract

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

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