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

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

  • Sci Transl Med. 2020 Apr 29;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883.
Timothy P Sheahan 1,  Amy C Sims 2,  Shuntai Zhou 3,  Rachel L Graham 2,  Andrea J Pruijssers 4,  Maria L Agostini 4,  Sarah R Leist 2,  Alexandra Schäfer 2,  Kenneth H Dinnon 3rd 2 5,  Laura J Stevens 4,  James D Chappell 4,  Xiaotao Lu 4,  Tia M Hughes 4,  Amelia S George 4,  Collin S Hill 3,  Stephanie A Montgomery 6,  Ariane J Brown 2,  Gregory R Bluemling 7 8,  Michael G Natchus 7,  Manohar Saindane 7,  Alexander A Kolykhalov 7 8,  George Painter 7 8 9,  Jennifer Harcourt 10,  Azaibi Tamin 10,  Natalie J Thornburg 10,  Ronald Swanstrom 3 11,  Mark R Denison 4,  Ralph S Baric 1 5
Affiliations

Affiliations

  • 1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.
  • 2 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 5 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 7 Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA 30322, USA.
  • 8 Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA 30322, USA.
  • 9 Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA.
  • 10 Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
  • 11 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
PMID: 32253226 DOI: 10.1126/scitranslmed.abb5883
Abstract

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-N4-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-N4-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.

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