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

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    Author
    Boras, Britton
    Jones, 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
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    Date
    2021-10-18
    Journal
    Nature Communications
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41467-021-26239-2
    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.
    Rights/Terms
    © 2021. The Author(s).
    Keyword
    3CL protease
    phosphate 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/10713/16970
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-021-26239-2
    Scopus Count
    Collections
    UMB Coronavirus Publications
    UMB Open Access Articles

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