Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

Nat Commun. 2021 Nov 5;12(1):6415. doi: 10.1038/s41467-021-26760-4.


Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Animals
  • Antiviral Agents / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Cell Line
  • Chlorocebus aethiops
  • Cricetinae
  • Disease Models, Animal
  • Female
  • Ferrets
  • Humans
  • Prodrugs / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / isolation & purification


  • Antiviral Agents
  • Prodrugs
  • GS-441524
  • Adenosine