To date, remdesivir is the only small molecule antiviral therapeutic approved by the FDA for the treatment of COVID-19 1. The socioeconomic and geopolitical impact of the pandemic is unprecedented and will most likely become fully evident only in postpandemic years. The global COVID-19 pandemic has resulted in far more than 150 million cases and an estimated 3.5 million deaths. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.
When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. 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. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery.
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