Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
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Published:2021-10-18
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Boras Britton, Jones Rhys M.ORCID, Anson Brandon J.ORCID, Arenson Dan, Aschenbrenner Lisa, Bakowski Malina A.ORCID, Beutler NathanORCID, Binder Joseph, Chen Emily, Eng HeatherORCID, Hammond Holly, Hammond Jennifer, Haupt Robert E., Hoffman RobertORCID, Kadar Eugene P., Kania Rob, Kimoto EmiORCID, Kirkpatrick Melanie G., Lanyon Lorraine, Lendy Emma K., Lillis Jonathan R., Logue JamesORCID, Luthra Suman A., Ma ChunlongORCID, Mason Stephen W., McGrath Marisa E.ORCID, Noell Stephen, Obach R. Scott, O’ Brien Matthew N., O’Connor Rebecca, Ogilvie KevinORCID, Owen Dafydd, Pettersson Martin, Reese Matthew R.ORCID, Rogers Thomas F.ORCID, Rosales RomelORCID, Rossulek Michelle I., Sathish Jean G., Shirai Norimitsu, Steppan Claire, Ticehurst Martyn, Updyke Lawrence W., Weston StuartORCID, Zhu Yuao, White Kris M.ORCID, García-Sastre AdolfoORCID, Wang JunORCID, Chatterjee Arnab K., Mesecar Andrew D., Frieman Matthew B.ORCID, Anderson Annaliesa S.ORCID, Allerton CharlotteORCID
Abstract
AbstractCOVID-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.
Funder
Pfizer U.S. Department of Defense U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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