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

Sheahan, Timothy P.; Sims, Amy C.; Zhou, Shuntai; Graham, Rachel L.; Pruijssers, Andrea J.; Agostini, Maria L.; Leist, Sarah R.; Schäfer, Alexandra; Dinnon, Kenneth H.; Stevens, Laura J.; Chappell, James D.; Lu, Xiaotao; Hughes, Tia M.; George, Amelia S.; Hill, Collin S.; Montgomery, Stephanie A.; 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, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N(4)-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-N(4)-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.