Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates

作者：Travis K. Warren, Robert Jordan, Michale Lo, Veronica Soloveva, Adrian S. Ray, Roy Bannister, Richard L. Mackman, Michel Perron, Kirsten M. Stray, Joy Y. Feng, Yili Xu, Jay Wells, Kelly S. Stuthman, Lisa S. Welch, Edward Doerffler, Lijun Zhang, Kwon Soo Chun, Hon C. Hui, Sean Neville, Willard Lew, Yeojin Park, Darius Babusis, Robert G. Strickley, Pamela Wong, S. Swaminathan, William Lee, Douglas L. Mayers, Tomáš Cihlář, Sina Bavari · 发表于：Open Forum Infectious Diseases · 年份：2015 · DOI：10.1093/ofid/ofv130.02 · 被引用次数：63 · 研究领域：Viral Infections and Outbreaks Research、Viral gastroenteritis research and epidemiology、Influenza Virus Research Studies

Background. The high case-fatality rate during the recent Ebola virus (EBOV) outbreak in West Africa is due in part to the lack of effective antiviral therapies. Antiviral screening against EBOV identified GS-5734, a prodrug of adenine nucleotide analog, as an inhibitor of pathogenic filoviruses. Method. In vitro activity was tested in filovirus-infected human endothelial cells, liver cells, and macrophages using quantitative GFP expression, PCR, and/or immunostaining. Intracellular metabolism was determined by LC/MS/MS and polymerase (pol) inhibition was tested in biochemical assays. Efficacy was assessed in blinded, placebo-controlled studies in EBOV-infected rhesus monkeys. Animals infected on Day 0 (N = 6 per treatment group) were treated once-daily for 12 days by intramuscular (IM) or intravenous (IV) injection. Survival (Day 28 postinfection), plasma viral RNA, and signs of Ebola virus disease (EVD) were monitored. Result. GS-5734 inhibits Ebola virus (Kikwit and Makona variants), Sudan, and Marburg virus (EC50 = 0.01 to 0.20 µM), and exhibits low cytotoxicity (CC50 = 2 to >20 µM) in multiple human cell types. The compound undergoes fast intracellular conversion to the nucleoside triphosphate metabolite that persists in cells (T1/2 > 10 h) and inhibits a surrogate viral RNA pol from respiratory syncytial virus (IC50 = 1 µM), but not host mitochondrial RNA or DNA pols (IC50 > 200 µM). IM treatment of EBOV-infected monkeys with 3 mg/kg GS-5734 initiated after the detectio...