• Timothy P Sheahan, Amy C Sims, Shuntai Zhou, Rachel L Graham, Andrea J Pruijssers, Maria L Agostini, Sarah R Leist, Alexandra Schäfer, Kenneth H Dinnon, Laura J Stevens, James D Chappell, Xiaotao Lu, Tia M Hughes, Amelia S George, Collin S Hill, Stephanie A Montgomery, Ariane J Brown, Gregory R Bluemling, Michael G Natchus, Manohar Saindane, Alexander A Kolykhalov, George Painter, Jennifer Harcourt, Azaibi Tamin, Natalie J Thornburg, Ronald Swanstrom, Mark R Denison, and Ralph S Baric.
• Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. sheahan@email.unc.edu rbaric@email.unc.edu.
• Sci Transl Med. 2020 Apr 29; 12 (541).

AbstractCoronaviruses (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.Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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