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. Herein, 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 coronavirus 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 coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
Science translational medicine. 2020 Apr 06 [Epub ahead of print]
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, Ralph S Baric
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. ., Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, TN, 37232,USA., Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, 30322, USA., Centers for Disease Control and Prevention, Division of Viral Diseases Atlanta GA.