Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Lo, Michael K.; Feldmann, Friederike; Gary, Joy; Jordan, Robert; Bannister, Roy; Cronin, Jacqueline; Patel, Nishi; Klena, John D.; Nichol, Stuart T.; Cihlář, Tomáš; Zaki, Sherif R.; Feldmann, Heinz; Spiropoulou, Christina F.; Wit, Emmie de

doi:10.1126/scitranslmed.aau9242

Cited by 208 publications

(175 citation statements)

References 19 publications

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“…Remdesivir, an adenosine analogue that can target the RNA-dependent RNA polymerase and block viral RNA synthesis, which has been a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV 5) infections in cultured cells [58], mice [59] and nonhuman primate models [60,61]. The Washington Department of Health administrated remdesivir intravenously firstly and found that remdesivir might have potential protection from SARS-CoV-2 infection [62].…”

Section: Virally Targeted Inhibitorsmentioning

confidence: 99%

Molecular immune pathogenesis and diagnosis of COVID-19

Geng

Peng

et al. 2020

Journal of Pharmaceutical Analysis

1,509

1,641

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Section: Virally Targeted Inhibitorsmentioning

confidence: 99%

Molecular immune pathogenesis and diagnosis of COVID-19

Geng

Peng

et al. 2020

Journal of Pharmaceutical Analysis

1,509

1,641

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“…Ebola virus (EBOV)) (5,8) and Paramyxoviridae (e.g. Nipah virus (NiV)) families (7,10,11), as well as in vitro activity against viruses in the Pneumoviridae (e.g. respiratory syncytial virus (RSV)) family (10).…”

mentioning

confidence: 99%

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Gordon

Tchesnokov

Woolner

et al. 2020

Journal of Biological Chemistry

866

1,070

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Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i؉3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2-Cmethylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.

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“…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). Studies in human airway epithelial cells showed that remdesivir also inhibits replication of a wide range of coronaviruses, including MERS-CoV (7).…”

mentioning

confidence: 99%

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Wit

Feldmann

Cronin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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825

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The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.MERS-CoV | antiviral | animal model | remdesivir | therapy

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Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Cited by 208 publications

References 19 publications

Molecular immune pathogenesis and diagnosis of COVID-19

Molecular immune pathogenesis and diagnosis of COVID-19

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

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