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

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.

Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites

“…To date, the control of FECV replication (which is the source of FIPV-causing mutant virus [45]) and the development of anti-coronavirus drugs [5,23,46] are two major preventive and therapeutic measures of FIPV. Since the coronavirus nsp5-encoded 3C-like protease (3CLpro) plays an important role in virus replication and immune evasion, 3CLpro is considered an attractive target for the development of anti-coronaviral therapeutics.…”

A Tale of Two Viruses: The Distinct Spike Glycoproteins of Feline Coronaviruses

“…[13]. While remaining a devastating disease in cat populations, recent reports describing the role of nucleoside analogs and protease inhibitors, and their potential as a treatment for FCoV infection have raised the possibility of preventing lethal FIP [15][16][17][18].…”

Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses

“…A few in vitro studies have also investigated the utility of remdesivir against non-human CoVs. For example, a study by Murphy et al reported anti-CoV activity of remdesivir's parent nucleoside, GS-441524, against an alphacoronavirus that only infects wild and domestic cats, the feline infectious peritonitis (FIP) virus (EC 50 = 0.78 μM; Table 1) [14]. In 2019, Brown et al observed some antiviral effects of remdesivir against SARS-like bat CoVs (specifically, Bat-CoV HKU3, Bat-CoV SCH014, and Bat-CoV WIV1) and MERS-like bat CoVs (specifically, Bat-CoV HKU5) [12].…”

“…Some veterinary studies have also examined the effects of the parent nucleoside, GS-441524, in cats with FIP, a condition associated with very high mortality in cats [14,16]. Gilead Sciences (Foster City, California) had provided this drug to researchers at the University of California, Davis to evaluate its potential utility in veterinary indications [35].…”

“…1c) [13]. The parent nucleoside, GS-441524, has displayed antiviral activity against SARS-CoV, Marburg virus, and feline infectious peritonitis virus, among others [9,[14][15][16]. A number of studies have examined the effects of these two drugs on coronaviruses (CoVs) both in vitro and in vivo using mouse and non-human primate animal models [9][10][11]13,17,18].…”