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

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, Romel Rosales, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Kris M. White, Adolfo García-Sastre, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson and Charlotte Allerton
Additional contact information
Britton Boras: Worldwide Research and Development, Pfizer Inc
Rhys M. Jones: Worldwide Research and Development, Pfizer Inc
Brandon J. Anson: Purdue University
Dan Arenson: Worldwide Research and Development, Pfizer Inc
Lisa Aschenbrenner: Worldwide Research and Development, Pfizer Inc
Malina A. Bakowski: Calibr, a division of The Scripps Research Institute
Nathan Beutler: The Scripps Research Institute
Joseph Binder: Worldwide Research and Development, Pfizer Inc
Emily Chen: Calibr, a division of The Scripps Research Institute
Heather Eng: Worldwide Research and Development, Pfizer Inc
Holly Hammond: Department of Microbiology and Immunology University of Maryland School of Medicine
Jennifer Hammond: Worldwide Research and Development, Pfizer Inc.
Robert E. Haupt: Department of Microbiology and Immunology University of Maryland School of Medicine
Robert Hoffman: Worldwide Research and Development, Pfizer Inc
Eugene P. Kadar: Worldwide Research and Development, Pfizer Inc
Rob Kania: Worldwide Research and Development, Pfizer Inc
Emi Kimoto: Worldwide Research and Development, Pfizer Inc
Melanie G. Kirkpatrick: Calibr, a division of The Scripps Research Institute
Lorraine Lanyon: Worldwide Research and Development, Pfizer Inc
Emma K. Lendy: Purdue University
Jonathan R. Lillis: Worldwide Research and Development, Pfizer Inc
James Logue: Department of Microbiology and Immunology University of Maryland School of Medicine
Suman A. Luthra: Worldwide Research and Development, Pfizer Inc
Chunlong Ma: University of Arizona
Stephen W. Mason: Worldwide Research and Development, Pfizer Inc
Marisa E. McGrath: Department of Microbiology and Immunology University of Maryland School of Medicine
Stephen Noell: Worldwide Research and Development, Pfizer Inc
R. Scott Obach: Worldwide Research and Development, Pfizer Inc
Matthew N. O’ Brien: Worldwide Research and Development, Pfizer Inc
Rebecca O’Connor: Worldwide Research and Development, Pfizer Inc
Kevin Ogilvie: Worldwide Research and Development, Pfizer Inc
Dafydd Owen: Worldwide Research and Development, Pfizer Inc
Martin Pettersson: Worldwide Research and Development, Pfizer Inc
Matthew R. Reese: Worldwide Research and Development, Pfizer Inc
Thomas F. Rogers: The Scripps Research Institute
Romel Rosales: Icahn School of Medicine at Mount Sinai
Michelle I. Rossulek: Worldwide Research and Development, Pfizer Inc
Jean G. Sathish: Worldwide Research and Development, Pfizer Inc.
Norimitsu Shirai: Worldwide Research and Development, Pfizer Inc
Claire Steppan: Worldwide Research and Development, Pfizer Inc
Martyn Ticehurst: Worldwide Research and Development, Pfizer Inc
Lawrence W. Updyke: Worldwide Research and Development, Pfizer Inc
Stuart Weston: Department of Microbiology and Immunology University of Maryland School of Medicine
Yuao Zhu: Worldwide Research and Development, Pfizer Inc.
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: Calibr, a division of The Scripps Research Institute
Andrew D. Mesecar: Purdue University
Matthew B. Frieman: Department of Microbiology and Immunology University of Maryland School of Medicine
Annaliesa S. Anderson: Worldwide Research and Development, Pfizer Inc.
Charlotte Allerton: Worldwide Research and Development, Pfizer Inc

Nature Communications, 2021, vol. 12, issue 1, 1-17

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. 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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-26239-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26239-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-26239-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().