The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies

Vet Microbiol. 2018 Jun;219:226-233. doi: 10.1016/j.vetmic.2018.04.026. Epub 2018 Apr 22.

Abstract

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.

Keywords: Cell culture; EC50; Experimental infection; FIP virus (FIPV); Feline infectious peritonitis (FIP); GS-441524; Laboratory cats; Nucleoside analog; Pharmacokinetics; Tri-phosphorylation.

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Ascitic Fluid / virology
  • Cats / virology
  • Cells, Cultured
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / veterinary
  • Coronavirus Infections / virology
  • Coronavirus, Feline / drug effects*
  • Coronavirus, Feline / immunology
  • Feline Infectious Peritonitis / drug therapy
  • Feline Infectious Peritonitis / virology*
  • Macrophages / drug effects
  • Macrophages / virology
  • Nucleosides / administration & dosage
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Nucleosides / therapeutic use*
  • Serogroup
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Nucleosides