Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26760-4
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- Department for Animal Research of Georgia State University
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Remdesivir is an antiviral drug approved for COVID-19 treatment, but its intravenous administration limits wider use. A study has shown that GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524, has good oral bioavailability and inhibits SARS-CoV-2 and variants of concern in ferrets, demonstrating therapeutic efficacy in a relevant animal model of SARS-CoV-2 infection.
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 gamma, 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. Remdesivir is an approved antiviral treatment for COVID-19, but it needs to be administered intravenously. Here, Cox et al. show that GS-621763, a prodrug of remdesivir parent nucleoside GS-441524 has good oral bioavailability and inhibits SARS-CoV-2 and variants of concerns in ferrets.
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