Paper

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

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

2021

Overview

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. Competing Interest Statement A.D.M has a sponsored program contract with Pfizer to test compounds for inhibition of coronavirus proteases. JW has a sponsored research agreement with Pfizer to test compounds for inhibition of coronavirus proteases. The Frieman Laboratory was funded by Pfizer for the work in this manuscript. Footnotes * One Sentence Summary: PF-07304814, a novel phosphate prodrug is disclosed as an investigational novel intravenous small molecule 3CL protease inhibitor for the potential treatment of COVID-19 and other coronavirus infections. * One small typo in the abstract. The compound ID number should be PF-00835231 and in the abstract the number is PF-00835321 in one place. This has been corrected in the abstract and in the manuscript. Version 3: Added in vivo efficacy data, section Activity of PF-00835231 in a mouse model of SARS-CoV-1 infection and Figure 4.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Antiviral activity / Coronaviridae / Coronaviruses / COVID-19 / Intravenous administration / Pandemics / Pharmacology and Toxicology / Proteinase inhibitors / Severe acute respiratory syndrome coronavirus 2 / Therapeutic applications