Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys

By Travis K Warren, R. Jordan, Michael K. Lo, A. Ray, R. Mackman, V. Soloveva, D. Siegel, M. Perron, R. Bannister, H. Hui and 52 more. Nature, 2016

1,409 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/38683c7e5f8ba5f2e4dde1eb2864f37b10ed0ada

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In Epidemiology

1. Ralph S. Baric
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Citations in the corpus

• The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus (2020, background): “M. G. has previously received funding from Gilead Sciences in support for the study of EBOV RdRp inhibition by RDV. 1 These authors contributed equally to this work.”
• Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19 (2020, neutral): “73 75 providing approximately 500-fold selectivity.”
• Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial (2020, background): “12, 13 In vitro, remdesivir inhibits all human and animal coronaviruses tested to date, including SARS-CoV-2, [13] [14] [15] and has shown antiviral and clinical effects in animal models of SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV infections.”
• Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses (2017, methodology): “studies (Scheme 2).(17) The glycosylation step employed the iodo-base 20 instead of the bromo”
• Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV (2020, methodology): “Remdesivir (RDV, GS-5734) is a broad-spectrum antiviral nucleotide prodrug with potent in vitro antiviral activity against a diverse panel of RNA viruses such as Ebola virus (EBOV), Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus (RSV), Nipah virus (NiV), and Hendra virus [16] [17] [18] .”
• SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat (2020, background): “76 μM, which is achievable in vivo based on a trial in nonhuman primate experiment [63, 69].”
• Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir (2020, background): “involved in RNA binding as well as residues comprising the catalytic active site are highly conserved in this viral RdRp(28, 29), thus highlighting the highly conserved mechanism of genome replication by RdRp in these diverse RNA virus, and suggesting a possibility to develop broad spectrum antivira”
• Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 (2022, background): “Remdesivir (GS-5734) is a broad-spectrum antiviral nucleotide prodrug with potent in vitro activity against a range of RNA viruses including Ebola virus, Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus, Nipah virus, and Hendra virus [58-60].”
• Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency (2020, background): “In this context, it is also important to note that our previous measurements with human mitochondrial RNA polymerase revealed high selectivity of ATP over RDV-TP (9), which is consistent with low levels of cytotoxicity of RDV (8, 14).”
• Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection (2020, background): “Remdesivir (GS-5734) is a nucleotide prodrug that has broad antiviral activity against viruses from different families in vitro (4), and therapeutic efficacy in nonhuman primate models of lethal Ebola virus and Nipah virus infection (5, 6).”