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.
【초록키워드】 COVID-19, SARS-CoV-2, coronavirus, Mutation, Antiviral, Ribonucleoside analog, SARS-CoV, Remdesivir, in vitro, antiviral activity, Prophylactic, MERS-CoV, NHC, RNA, Outbreaks, Pulmonary function, mice, zoonotic, therapeutic, EIDD-1931, CoV, EIDD-2801, in vivo, inhibitor, utility, disease, mechanism, Mutagenesis, administration, Frequency, host cell, virus titer, CoVs, multiple coronaviruses, zoonotic coronaviruses, Body weight loss, oral bioavailability, effective, highlight, resulting, reduced, in viral, Decreased, 【제목키워드】 SARS-CoV-2, Antiviral, mice, Cell culture, multiple coronaviruses, inhibit, human airway epithelial,