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.
Robert M Cox  1 ,  Josef D Wolf  1 ,  Carolin M Lieber  1 ,  Julien Sourimant  1 ,  Michelle J Lin  2 ,  Darius Babusis  3 ,  Venice DuPont  3 ,  Julie Chan  3 ,  Kim T Barrett  3 ,  Diane Lye  3 ,  Rao Kalla  3 ,  Kwon Chun  3 ,  Richard L Mackman  3 ,  Chengjin Ye  4 ,  Tomas Cihlar  3 ,  Luis Martinez-Sobrido  4 ,  Alexander L Greninger  2 ,  John P Bilello  3 ,  Richard K Plemper  5
Affiliations
  • 1. Center for Translational Antiviral Research, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
  • 2. Virology Division, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • 3. Gilead Sciences Inc, Foster City, CA, USA.
  • 4. Texas Biomedical Research Institute, San Antonio, TX, USA.
  • 5. Center for Translational Antiviral Research, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. [email protected].
PMID: 34741049 DOI: 10.1038/s41467-021-26760-4
Abstract

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.

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