An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan,
Amy C. Sims,
Rachel L. Graham,
Collin S. Hill,
Sarah R. Leist,
Kenneth H. Dinnon,
Stephanie A. Montgomery,
Maria L Agostini,
Andrea J. Pruijssers,
James D. Chapell,
Ariane J Brown,
Gregory R. Bluemling,
Michael G. Natchus,
Alexander A. Kolykhalov,
Mark R. Denison,
Ralph S. Baric
Posted 20 Mar 2020
bioRxiv DOI: 10.1101/2020.03.19.997890
Posted 20 Mar 2020
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog Beta-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 another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (Beta-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. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
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