Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

• Published in: Nature (London) Vol. 531; no. 7594; pp. 381 - 385
• Main Authors: Warren, Travis K., Jordan, Robert, Lo, Michael K., Ray, Adrian S., Mackman, Richard L., Soloveva, Veronica, Siegel, Dustin, Perron, Michel, Bannister, Roy, Hui, Hon C., Larson, Nate, Strickley, Robert, Wells, Jay, Stuthman, Kelly S., Van Tongeren, Sean A., Garza, Nicole L., Donnelly, Ginger, Shurtleff, Amy C., Retterer, Cary J., Gharaibeh, Dima, Zamani, Rouzbeh, Kenny, Tara, Eaton, Brett P., Grimes, Elizabeth, Welch, Lisa S., Gomba, Laura, Wilhelmsen, Catherine L., Nichols, Donald K., Nuss, Jonathan E., Nagle, Elyse R., Kugelman, Jeffrey R., Palacios, Gustavo, Doerffler, Edward, Neville, Sean, Carra, Ernest, Clarke, Michael O., Zhang, Lijun, Lew, Willard, Ross, Bruce, Wang, Queenie, Chun, Kwon, Wolfe, Lydia, Babusis, Darius, Park, Yeojin, Stray, Kirsten M., Trancheva, Iva, Feng, Joy Y., Barauskas, Ona, Xu, Yili, Wong, Pamela, Braun, Molly R., Flint, Mike, McMullan, Laura K., Chen, Shan-Shan, Fearns, Rachel, Swaminathan, Swami, Mayers, Douglas L., Spiropoulou, Christina F., Lee, William A., Nichol, Stuart T., Cihlar, Tomas, Bavari, Sina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.03.2016; Nature Publishing Group
• Subjects: 631/154/433; 631/326/596/2555; 692/308/153; 692/699/255/2514; Alanine - analogs & derivatives; Alanine - pharmacokinetics; Alanine - pharmacology; Alanine - therapeutic use; Amino Acid Sequence; Analysis; Animal diseases; Animals; Antiviral agents; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Care and treatment; Cell Line, Tumor; Control; Drug therapy; Ebola virus; Ebolavirus - drug effects; Female; Geographical distribution; Health aspects; HeLa Cells; Hemorrhagic Fever, Ebola - drug therapy; Hemorrhagic Fever, Ebola - prevention & control; Humanities and Social Sciences; Humans; Intravenous administration; letter; Macaca mulatta - virology; Male; Molecular Sequence Data; Monkeys & apes; multidisciplinary; Organ Specificity; Pathogens; Pharmacokinetics; Prodrugs; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Prodrugs - therapeutic use; Rhesus monkey; Ribonucleotides - pharmacokinetics; Ribonucleotides - pharmacology; Ribonucleotides - therapeutic use; RNA polymerase; Science; Testing; Treatment outcome; Africa; United States; West Africa
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17180

The discovery is reported of a small molecule drug, GS-5734, which has antiviral activity against Ebola virus and other filoviruses, and is capable of providing post-exposure therapeutic protection against lethal disease in 100% of drug-treated nonhuman primates infected with Ebola virus; the drug targets viral RNA polymerase and can distribute to sanctuary sites (such as testes, eyes and brain), suggesting that it may be able to clear persistent virus infection. A drug active against Ebola virus These authors report the discovery of a small-molecule drug, GS-5734, which has antiviral activity against Ebola and other filoviruses, and is capable of providing post-exposure protection against Ebola virus in 100% of infected macaques tested. Now in clinical trials ( http://go.nature.com/PEW2Oi ), the drug targets the viral RNA-dependent RNA polymerase and is readily scalable for future outbreaks. GS-5734 is able to distribute to sanctuary sites for viral replication including the testes, eye and brain, offering the hope that this drug may also be able to clear recrudescent and persistent virus infection. The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae 1 . No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro , and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg −1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.