生物活性

• 描述GS-5734 is a monophosphoramidate prodrug of an adenosine analog that exhibits antiviral activity against a wide range of filoviruses including Marburg virus and multiple variants of Ebola virus. It inhibited replication of Ebola virus in several human cell types including primary macrophages, Hela cells, and human endothelial cells with EC₅₀ values of 0.06 to 0.14μM. In liver Huh-7 cells infected with the Makona variant of Ebola virus, treatment with GS-5734 resulted in a dose-dependent reduction in viral RNA production and the amount of infectious viruses. GS-5734 exhibited a short plasma half-life (t_1/2 = 0.39h) in rhesus monkeys administrated with a 10mg/kg dose via intravenous injection. It also rapidly distributed into peripheral blood mononuclear cells and converted to nucleoside triphosphates within 2h of dose administration. In rhesus monkeys intramuscularly inoculated with Ebola virus, treatment with 3mg/kg GS-5734 beginning on day 0 or day 2 conferred an antiviral effect and improved survival (33% in the day 0 group and 66% in the day 2 group) relative to vehicle-treated animals. Animals in which GS-5734 was administered at a loading dose of 10mg/kg followed by once-daily 3mg/kg doses beginning either 2 days or 3 days after virus exposure survived to the end of the in-life phase. Rhesus monkeys treated with 10mg/kg doses of GS-5734 beginning 3 days following virus exposure also survived to 28 days following virus exposure. This group also showed ameliorated Ebola virus disease-related clinical disease signs and markers of coagulopathy and end-organ pathophysiology compared to other GS-5734-treated monkeys.^[1]
• 作用机制GS-5734 is a potent and selective inhibitor of Ebola virus. It inhibits replication of Ebola virus by targeting its RNA-dependent RNA-polymerases and inhibiting viral RNA synthesis following efficient intracellular conversion to active nucleoside triphosphates. ^[1]