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

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

Science translational medicine (2020-04-08)
Timothy P Sheahan, Amy C Sims, Shuntai Zhou, Rachel L Graham, Andrea J Pruijssers, Maria L Agostini, Sarah R Leist, Alexandra Schäfer, Kenneth H Dinnon, Laura J Stevens, James D Chappell, Xiaotao Lu, Tia M Hughes, Amelia S George, Collin S Hill, Stephanie A Montgomery, Ariane J Brown, Gregory R Bluemling, Michael G Natchus, Manohar Saindane, Alexander A Kolykhalov, George Painter, Jennifer Harcourt, Azaibi Tamin, Natalie J Thornburg, Ronald Swanstrom, Mark R Denison, Ralph S Baric
RESUMEN

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.

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Sigma-Aldrich
EIDD-2801, ≥98% (HPLC)

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