Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
Author
Boras, BrittonJones, Rhys M
Anson, Brandon J
Arenson, Dan
Aschenbrenner, Lisa
Bakowski, Malina A
Beutler, Nathan
Binder, Joseph
Chen, Emily
Eng, Heather
Hammond, Holly
Hammond, Jennifer
Haupt, Robert E
Hoffman, Robert
Kadar, Eugene P
Kania, Rob
Kimoto, Emi
Kirkpatrick, Melanie G
Lanyon, Lorraine
Lendy, Emma K
Lillis, Jonathan R
Logue, James
Luthra, Suman A
Ma, Chunlong
Mason, Stephen W
McGrath, Marisa E
Noell, Stephen
Obach, R Scott
O' Brien, Matthew N
O'Connor, Rebecca
Ogilvie, Kevin
Owen, Dafydd
Pettersson, Martin
Reese, Matthew R
Rogers, Thomas F
Rosales, Romel
Rossulek, Michelle I
Sathish, Jean G
Shirai, Norimitsu
Steppan, Claire
Ticehurst, Martyn
Updyke, Lawrence W
Weston, Stuart
Zhu, Yuao
White, Kris M
García-Sastre, Adolfo
Wang, Jun
Chatterjee, Arnab K
Mesecar, Andrew D
Frieman, Matthew B
Anderson, Annaliesa S
Allerton, Charlotte
Date
2021-10-18Journal
Nature CommunicationsPublisher
Springer NatureType
Article
Metadata
Show full item recordAbstract
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.Rights/Terms
© 2021. The Author(s).Keyword
3CL proteasephosphate prodrug PF-07304814
PF-00835231
COVID-19
Prodrugs--therapeutic use
SARS-CoV-2--drug effects
Viral Protease Inhibitors
Identifier to cite or link to this item
http://hdl.handle.net/10713/16970ae974a485f413a2113503eed53cd6c53
10.1038/s41467-021-26239-2
Scopus Count
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