An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus

Sheahan, Timothy P.; Sims, Amy C.; Zhou, Shuntai; Graham, Rachel L.; Hill, Collin S.; Leist, Sarah R.; Schäfer, Alexandra; Dinnon, Kenneth H.; Montgomery, Stephanie A.; Agostini, Maria L.; Pruijssers, Andrea J.; Chapell, James D.; Brown, Ariane J.; Bluemling, Gregory R.; Natchus, Michael G.; Saindane, Manohar; Kolykhalov, Alexander A.; Painter, George; Harcourt, Jennifer; Tamin, Azaibi; Thornburg, Natalie J.; Swanstrom, Ronald; Denison, Mark R.; Baric, Ralph S.

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 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 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 (b-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.