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

Nat Commun. 2021 Oct 18;12(1):6055. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Monophosphate / administration & dosage
  • Adenosine Monophosphate / adverse effects
  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacokinetics
  • Alanine / administration & dosage
  • Alanine / adverse effects
  • Alanine / analogs & derivatives
  • Alanine / pharmacokinetics
  • Animals
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Chlorocebus aethiops
  • Coronavirus 229E, Human / drug effects
  • Coronavirus 229E, Human / enzymology
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus Protease Inhibitors / administration & dosage*
  • Coronavirus Protease Inhibitors / adverse effects
  • Coronavirus Protease Inhibitors / pharmacokinetics
  • Disease Models, Animal
  • Drug Design
  • Drug Synergism
  • Drug Therapy, Combination
  • HeLa Cells
  • Humans
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Infusions, Intravenous
  • Leucine / administration & dosage*
  • Leucine / adverse effects
  • Leucine / pharmacokinetics
  • Mice
  • Pyrrolidinones / administration & dosage*
  • Pyrrolidinones / adverse effects
  • Pyrrolidinones / pharmacokinetics
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / enzymology
  • Severe acute respiratory syndrome-related coronavirus / drug effects
  • Severe acute respiratory syndrome-related coronavirus / enzymology
  • Vero Cells

Substances

  • Coronavirus Protease Inhibitors
  • Indoles
  • Pyrrolidinones
  • remdesivir
  • Adenosine Monophosphate
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
  • Leucine
  • Alanine
  • lufotrelvir