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

Britton Boras(Pfizer (United States)), Rhys Jones(Pfizer (United States)), Brandon J. Anson(Purdue University West Lafayette), Dan Arenson(Pfizer (United States)), Lisa Aschenbrenner(Pfizer (United States)), Malina A. Bakowski(Scripps Research Institute), Nathan Beutler(Scripps Research Institute), Joseph Binder(Pfizer (United States)), Emily Chen(Scripps Research Institute), Heather Eng(Pfizer (United States)), Holly Hammond(University of Maryland, Baltimore), Jennifer Hammond(Pfizer (United States)), Robert Haupt(University of Maryland, Baltimore), Robert L. Hoffman(Pfizer (United States)), Eugene P. Kadar(Pfizer (United States)), Rob Kania(Pfizer (United States)), Emi Kimoto(Pfizer (United States)), Melanie G. Kirkpatrick(Scripps Research Institute), Lorraine F. Lanyon(Pfizer (United States)), Emma K. Lendy(Purdue University West Lafayette), Jonathan R. Lillis(Pfizer (United Kingdom)), James Logue(University of Maryland, Baltimore), Suman Luthra(Pfizer (United States)), Chunlong Ma(University of Arizona), Stephen W. Mason(Pfizer (United States)), Marisa E. McGrath(University of Maryland, Baltimore), Stephen Noell(Pfizer (United States)), R. Scott Obach(Pfizer (United States)), Matthew N. O’Brien(Pfizer (United States)), Rebecca E. O’Connor(Pfizer (United States)), Kevin Ogilvie(Pfizer (United States)), Dafydd R. Owen(Pfizer (United States)), Martin Pettersson(Pfizer (United States)), Matthew R. Reese(Pfizer (United States)), Thomas F. Rogers(Scripps Research Institute), Michelle I. Rossulek(Pfizer (United States)), Jean G. Sathish(Pfizer (United States)), Norimitsu Shirai(Pfizer (United States)), Claire M. Steppan(Pfizer (United States)), Martyn D. Ticehurst(Pfizer (United Kingdom)), Lawrence W. Updyke(Pfizer (United States)), Stuart Weston(University of Maryland, Baltimore), Yuao Zhu(Pfizer (United States)), Jun Wang(University of Arizona), Arnab K. Chatterjee(Scripps Research Institute), Andrew D. Mesecar(Purdue University West Lafayette), Matthew B. Frieman(University of Maryland, Baltimore), Annaliesa S. Anderson(Pfizer (United States)), Charlotte Allerton(Pfizer (United States))
bioRxiv (Cold Spring Harbor Laboratory)
September 13, 2020
10.1101/2020.09.12.293498
Cited by 159Open Access
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Abstract

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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