Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-<i>f</i>][triazin-4-amino] Adenine <i>C</i>-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

Siegel, Dustin S.; Hui, Hon; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon Soo; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce S.; Wang, Queenie; Wolfe, Lydia C.; Jordan, Robert; Soloveva, Veronica; Knox, John R.; Perry, Jason K.; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert G.; Swaminathan, S.; Lee, William A.; Bavari, Sina; Cihlář, Tomáš; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L.

doi:10.1021/acs.jmedchem.6b01594

Cited by 591 publications

(595 citation statements)

References 36 publications

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“…One study reported the compassionate use of GS-5734 in combination with ZMapp and a convalescent buffy coat transfusion in a newborn baby who survived EBOV infection 177 . GS-5734 is currently being used in West Africa in a trial called PREVAIL for men with persistent EBOV RNA in semen 178 .…”

Section: Gs-5734mentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Gs-5734mentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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“…For the RdRp target in the genus Betacornavirus, there are several potential drugs or compounds, including favipiravir, ribavirin, penciclovir, galidesivir, remdesivir, 6'-fluorinatedaristeromycin analogs, and acyclovir fleximer analogs [12]. Remdesivir (GS-5734), the phosphoramidate prodrug of an adenosine C-nucleoside [13], has a structure similar to tenofovir alafenamide, which is a nucleotide analog of adenosine 5-monophosphate with antiviral activity against hepatitis B virus and human immunodeficiency virus. It was developed by Gilead Science Inc. and has not been licensed or approved anywhere for now.…”

Section: Rna Polymerasesmentioning

confidence: 99%

Arguments in favour of remdesivir for treating SARS-CoV-2 infections

Rolain

Lee

et al. 2020

International Journal of Antimicrobial Agents

303

248

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“…GS-441524 is also a broad-spectrum inhibitor of a variety of RNA viruses from four families (Filoviridae, Flaviviridae, Paramyxoviridae, and Pneumoviridae), including HCV and RSV. 163,164 However, the addition of a 2 0 -C-methyl group, as in the case of the GS-6620, 165,166 significantly reduces the antiviral spectrum to HCV only. The relatively weak antiviral activity of GS-441524 across all viruses (0.5-50 mM EC 50 ) was attributed to its inefficient intracellular phosphorylation, which could be improved by adding a monophosphate prodrug to the parent nucleoside.…”

Section: Gs-5734 For Ebola Virus and Covmentioning

confidence: 99%

Nucleosides for the treatment of respiratory RNA virus infections

Jordan

Stevens

Deval

2018

Antivir Chem Chemother

127

105

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Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.

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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

Cited by 591 publications

References 36 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Arguments in favour of remdesivir for treating SARS-CoV-2 infections

Nucleosides for the treatment of respiratory RNA virus infections

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