An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
Top Cited Papers
Open Access
- 29 April 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (541)
- https://doi.org/10.1126/scitranslmed.abb5883
Abstract
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.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (5U19AI109680)
- National Institute of Allergy and Infectious Diseases (5R01AI132178)
- National Institute of Allergy and Infectious Diseases (AI108197)
- National Institute of Allergy and Infectious Diseases (HHSN272201500008C)
- National Institute of Allergy and Infectious Diseases (1U19AI142759)
- National Institute of Allergy and Infectious Diseases (F31AI133952)
- National Institute of Allergy and Infectious Diseases (T32AI112541)
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