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.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Monophosphate / administration & dosage
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Adenosine Monophosphate / adverse effects
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Adenosine Monophosphate / analogs & derivatives
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Adenosine Monophosphate / pharmacokinetics
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Alanine / administration & dosage
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Alanine / adverse effects
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Alanine / analogs & derivatives
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Alanine / pharmacokinetics
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Animals
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COVID-19 / virology
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COVID-19 Drug Treatment*
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Chlorocebus aethiops
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Coronavirus 229E, Human / drug effects
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Coronavirus 229E, Human / enzymology
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Coronavirus 3C Proteases / antagonists & inhibitors*
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Coronavirus Protease Inhibitors / administration & dosage*
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Coronavirus Protease Inhibitors / adverse effects
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Coronavirus Protease Inhibitors / pharmacokinetics
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Disease Models, Animal
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Drug Design
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Drug Synergism
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Drug Therapy, Combination
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HeLa Cells
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Humans
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Indoles / administration & dosage*
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Indoles / adverse effects
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Indoles / pharmacokinetics
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Infusions, Intravenous
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Leucine / administration & dosage*
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Leucine / adverse effects
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Leucine / pharmacokinetics
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Mice
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Pyrrolidinones / administration & dosage*
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Pyrrolidinones / adverse effects
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Pyrrolidinones / pharmacokinetics
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SARS-CoV-2 / drug effects
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SARS-CoV-2 / enzymology
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Severe acute respiratory syndrome-related coronavirus / drug effects
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Severe acute respiratory syndrome-related coronavirus / enzymology
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Vero Cells
Substances
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Coronavirus Protease Inhibitors
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Indoles
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Pyrrolidinones
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remdesivir
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Adenosine Monophosphate
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3C-like proteinase, SARS-CoV-2
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Coronavirus 3C Proteases
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Leucine
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Alanine
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lufotrelvir