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. 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.
【저자키워드】 SARS-CoV-2, antivirals, 【초록키워드】 COVID-19, Treatment, Efficacy, Antiviral, VoC, SARS-COV-2 infection, variants of concern, Remdesivir, triphosphate, lung, Transmission, animal model, Antiviral treatment, anti-SARS-CoV-2, variants, COVID-19 treatment, Lungs, Cell culture, GS-441524, virus replication, plasma, oral, organoids, patients, mechanism, metabolite, boost, prodrug, administration, Contact, intravenous, oral administration, Human airway epithelium, Therapeutic benefit, therapeutic efficacy, nucleoside, ferrets, early administration, intravenously, parent nucleoside, Administered, oral bioavailability, block, Prevent, inhibit, approved, reduce, dosed, inhibit SARS-CoV-2, 【제목키워드】 ferret, oral,