Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19

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), Romel Rosales(Icahn School of Medicine at Mount Sinai), 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)), Kris M. White(Icahn School of Medicine at Mount Sinai), Adolfo García‐Sastre(Icahn School of Medicine at Mount Sinai), 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))
Nature Communications
October 18, 2021
10.1038/s41467-021-26239-2
Cited by 295Open Access
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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. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

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