Medical infrastructures in Guinea, Sierra Leone, and Liberia were seriously impacted by a loss of >500 healthcare workers 1. The 2013–2016 outbreak of EVD in West Africa was the largest and most complex EBOV outbreak in the recorded history of the disease, with >28,000 EVD cases and >11,000 reported deaths 1. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing. 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. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. 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. 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.
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. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. 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. Nature volume 531, pages 381–385 ( 2016) Cite this article Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys
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