An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Details

• Alternative Title:
  Sci Transl Med
• Personal Author:
  Sheahan, Timothy P. ; Sims, Amy C. ; Zhou, Shuntai ; Graham, Rachel L. ; Pruijssers, Andrea J. ; Agostini, Maria L. ; Leist, Sarah R. ; Schäfer, Alexandra ; Dinnon, Kenneth H. ; Stevens, Laura J. ; Chappell, James D. ; Lu, Xiaotao ; Hughes, Tia M. ; George, Amelia S. ; Hill, Collin S. ; Montgomery, Stephanie A. ; Brown, Ariane J. ; Bluemling, Gregory R. ; Natchus, Michael G. ; Saindane, Manohar ; Kolykhalov, Alexander A. ; Painter, George ; Harcourt, Jennifer ; Tamin, Azaibi ; Thornburg, Natalie J. ; Swanstrom, Ronald ; Denison, Mark R. ; Baric, Ralph S.
• Description:
  Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β-d-N|-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N|-hydroxycytidine-5'-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.
• Subjects:
  Adenosine Monophosphate Alanine Animals Antibiotic Prophylaxis Antiviral Agents Betacoronavirus Cell Line Coronavirus Infections COVID-19 Cytidine Disease Models, Animal Drug Resistance, Viral Humans Lung Mice Mice, Inbred C57BL Middle East Respiratory Syndrome Coronavirus Models, Molecular Mutation Pandemics Pneumonia, Viral Primary Cell Culture Random Allocation Respiratory System Ribonucleosides RNA, Viral RNA Replicase Virus Replication

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• Source:
  Sci Transl Med. 2020; 12(541)
• Pubmed ID:
  32253226
• Pubmed Central ID:
  PMC7199910
• Document Type:
  Journal Article
• Funding:
  R01 AI108197/AI/NIAID NIH HHS/United States ; R01 AI132178/AI/NIAID NIH HHS/United States ; U19 AI109680/AI/NIAID NIH HHS/United States ; U19 AI142759/AI/NIAID NIH HHS/United States
• Volume:
  12
• Issue:
  541
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:63c4ef37035ae09ab0a2dac1cf30576be50fdc36638f166727cd41c865a08577
• Download URL:
  https://stacks.cdc.gov/view/cdc/87027/cdc_87027_DS1.pdf
• File Type:
  [PDF - 511.02 KB ]