2. Academic Validation
  3. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

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

  • Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180.
Travis K Warren 1 2,  Robert Jordan 3,  Michael K Lo 4,  Adrian S Ray 3,  Richard L Mackman 3,  Veronica Soloveva 1 2,  Dustin Siegel 3,  Michel Perron 3,  Roy Bannister 3,  Hon C Hui 3,  Nate Larson 3,  Robert Strickley 3,  Jay Wells 1,  Kelly S Stuthman 1,  Sean A Van Tongeren 1,  Nicole L Garza 1,  Ginger Donnelly 1,  Amy C Shurtleff 1,  Cary J Retterer 1,  Dima Gharaibeh 1,  Rouzbeh Zamani 1,  Tara Kenny 1,  Brett P Eaton 1,  Elizabeth Grimes 1,  Lisa S Welch 1,  Laura Gomba 1 2,  Catherine L Wilhelmsen 1,  Donald K Nichols 1,  Jonathan E Nuss 1 2,  Elyse R Nagle 1,  Jeffrey R Kugelman 1,  Gustavo Palacios 1,  Edward Doerffler 3,  Sean Neville 3,  Ernest Carra 3,  Michael O Clarke 3,  Lijun Zhang 3,  Willard Lew 3,  Bruce Ross 3,  Queenie Wang 3,  Kwon Chun 3,  Lydia Wolfe 3,  Darius Babusis 3,  Yeojin Park 3,  Kirsten M Stray 3,  Iva Trancheva 3,  Joy Y Feng 3,  Ona Barauskas 3,  Yili Xu 3,  Pamela Wong 3,  Molly R Braun 5,  Mike Flint 4,  Laura K McMullan 4,  Shan-Shan Chen 3,  Rachel Fearns 5,  Swami Swaminathan 3,  Douglas L Mayers 1,  Christina F Spiropoulou 4,  William A Lee 3,  Stuart T Nichol 4,  Tomas Cihlar 3,  Sina Bavari 1 2
Affiliations

Affiliations

  • 1 United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
  • 2 United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
  • 3 Gilead Sciences, Foster City, California 94404, USA.
  • 4 Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
  • 5 Boston University School of Medicine, Boston, Massachusetts 02118, USA.
PMID: 26934220 DOI: 10.1038/nature17180
Abstract

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. 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.

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