An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
Timothy P. Sheahan1,*,†, Amy C. Sims1,*,‡, Shuntai Zhou2, Rachel L. Graham1, Andrea J. Pruijssers3, Maria L. Agostini3, Sarah R. Leist1, Alexandra Schäfer1, Kenneth H. Dinnon III1,4, Laura J. Stevens3, James D. Chappell3, Xiaotao Lu3, Tia M. Hughes3, Amelia S. George3, Collin S. Hill2, Stephanie A. Montgomery5, Ariane J. Brown1, Gregory R. Bluemling6,7, Michael G. Natchus6, Manohar Saindane6, Alexander A. Kolykhalov6,7, George Painter6,7,8, Jennifer Harcourt9, Azaibi Tamin9, Natalie J. Thornburg9, Ronald Swanstrom2,10, Mark R. Denison3 and Ralph S. Baric1,4,†
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Science Translational Medicine 29 Apr 2020:
Vol. 12, Issue 541, eabb5883
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.
