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

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

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. rplemper@gsu.edu.
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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