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]
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02818582	Persistent Ebola Virus	Phase 2	Recruiting	June 1, 2019	Guinea ... more >> National Center for Trainingand Research in Rural Health Recruiting Conakry, Guinea, CKRY 001 Contact: Facely Tolno, MD    Not Listed       Physician at the service of the Infectious and Tropical Diseases Recruiting Conakry, Guinea, CKRY 001 Contact: Facely Tolno, MD    Not Listed    tolnof1905@gmail.com    Liberia JFK Hospital Recruiting Monrovia, Liberia, FWA00021658 Contact: Elizabeth Higgs, M.D.    (301) 402-8372    ehiggs@niaid.nih.gov    Duport Road PREVAIL Clinic Recruiting Paynesville, Liberia Contact: Dehkontee Gayedyu-Dennis, M.D.    +231886538810    dehkoden@gmail.com Collapse <<
  NCT04257656	2019-nCov	Phase 3	Recruiting	May 1, 2020	Bin Cao Beijing, Beijing, Chin... more >>a Collapse <<
  NCT04252664	2019-nCoV	Phase 3	Recruiting	April 27, 2020	Jin Yin-tan hospital Wu Han, H... more >>ubei, China Collapse <<

• 更多
• 参考文献

• [1] Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys [published correction appears in ACS Chem Biol. 2016 May 20;11(5):1463]. Nature. 2016;531(7594):381-385. doi:10.1038/nature17180