Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

作者：Maria L. Agostini, Andrea J. Pruijssers, James D. Chappell, Jennifer Gribble, Xiaotao Lu, Erica L. Andres, Gregory R. Bluemling, Mark A. Lockwood, Timothy P. Sheahan, Amy Sims, Michael G. Natchus, Manohar Saindane, Alexander A. Kolykhalov, George R. Painter, Ralph S. Baric, Mark R. Denison · 发表于：Journal of Virology · 年份：2019 · DOI：10.1128/jvi.01348-19 · 被引用次数：355 · 研究领域：Plant Virus Research Studies、SARS-CoV-2 and COVID-19 Research、RNA Interference and Gene Delivery

The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections. Here, we demonstrate the potent antiviral activity of a broad-spectrum ribonucleoside analogue, β- d - N 4 -hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only low-level resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections.