title: Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.
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.
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.|United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
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authors.initials: TK
authors.lastname: Warren
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lo
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.|United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
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authors.initials: V
authors.lastname: Soloveva
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.lastname: Siegel
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.initials: HC
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.lastname: Larson
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.lastname: Strickley
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.lastname: Wells
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: KS
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: SA
authors.lastname: Van Tongeren
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: AC
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: BP
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Welch
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.|United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: CL
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.initials: DK
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.|United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.
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authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
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authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA.|United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA.
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mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives; D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D029043:Ebolavirus / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D008253:Macaca mulatta / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012265:Ribonucleotides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D012265:Ribonucleotides; C000606551:remdesivir; D000249:Adenosine Monophosphate; D000409:Alanine