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

• Type of Material: Article
• Authors: Timothy P. Sheahan, University of North Carolina; Amy C. Sims, University of North Carolina; Shuntai Zhou, University of North Carolina; Rachel L. Graham, University of North Carolina; Andrea J. Pruijssers, Vanderbilt University; Maria L. Agostini, Vanderbilt University; Sarah R. Leist, University of North Carolina; Alexandra Schafer, University of North Carolina; Kenneth H. Dinnon III, University of North Carolina; Laura J. Stevens, Vanderbilt University; James D. Chappell, Vanderbilt University; Xiaotao Lu, Vanderbilt University; Tia M. Hughes, Vanderbilt University; Amelia S George, Vanderbilt University; Collin S. Hill, University of North Carolina; Stephanie A. Montgomery, University of North Carolina; Ariane J. Brown, University of North Carolina; Gregory Bluemling, Emory University; Michael Natchus, Emory University; Manohar Saindane, Emory University; Alexander A. Kolykhalov, Emory University; George Painter, Emory University; Jennifer Harcourt, Centers for Disease Control and Prevention; Azaibi Tamin, Centers for Disease Control and Prevention; Natalie J. Thornburg, Centers for Disease Control and Prevention; Ronald Swanstrom, University of North Carolina; Mark R. Denison, Vanderbilt University; Ralph S. Baric, University of North Carolina
• Language: English
• Date: 2020-04-29
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.abb5883
• Title of Journal or Parent Work: SCIENCE TRANSLATIONAL MEDICINE
• Volume: 12
• Issue: 541
• Grant/Funding Information: We would like to acknowledge the following funding sources, Antiviral Drug Discovery and Development Center (5U19AI109680 and (1U19AI142759) awarded to M.D. and R.S.B, a partnership grant from the National Institutes of Allergy and Infectious Disease (NIAID, 5R01AI132178) awarded to T.P.S. and R.S.B. and an NIAID R01 grant (AI108197) awarded to M.D. and R.S.B.. NIAID contract, HHSN272201500008C, was awarded to G.P. and The Emory institute for Drug Development and a subcontract from this was awarded to R.S.B. and M.R.D. M.L.A. was funded through training grants F31AI133952 and T32AI112541. The Marsico lung Institute Tissue Procurement and Cell Culture Core is supported by NIH grant DK065988 and Cystic Fibrosis Foundation grant BOUCHE15RO.
• Keywords: PNEUMONIA; LENGTH INFECTIOUS CDNA; MERS-COV; EBOLA-VIRUS; SARS; VIRAL LOAD; Medicine, Research & Experimental; Cell Biology; RESPIRATORY-TRACT; Science & Technology; RHESUS; Life Sciences & Biomedicine; FEATURES; Research & Experimental Medicine
• Research Categories: Biology, Virology; Biology, Cell

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, MERSCoV, 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 SARSCoV-2 and other future zoonotic CoVs.