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Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance
Open accessAbstract
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.
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Cites
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Bolger, A. M., Lohse, M., & Usadel, B. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu170 · Cited by 65,548
SARS: systematic review of treatment effects
Stockman, L. J., Bellamy, R., & Garner, P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030343 · Cited by 1,217
Domingo, E., Sheldon, J., & Perales, C. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05023-11 · Cited by 1,009
SARS-like WIV1-CoV poised for human emergence
Menachery, V. D., Yount, B. L., Sims, A. C., Debbink, K., Agnihothram, S. S., Gralinski, L. E., Graham, R. L., Scobey, T., Plante, J. A., Royal, S. R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1517719113 · Cited by 418
Self-citationThe contribution of epistasis to the architecture of fitness in an RNA virus
Sanjuán, R., Moya, A., & Elena, S. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404125101 · Cited by 233
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Wang, Y., Li, P., Solanki, K., Li, Y., Ma, Z., Peppelenbosch, M. P., Baig, M. S., & Pan, Q. (2021) · Virology · doi:10.1016/j.virol.2021.09.009 · Cited by 46
Metadata
- Authors
- Agostini, M. L., Pruijssers, A. J., Chappell, J. D., Gribble, J., Lu, X., Andres, E. L., Bluemling, G. R., Lockwood, M. A., Sheahan, T. P., Sims, A. C., Natchus, M. G., Saindane, M., Kolykhalov, A. A., Painter, G. R., Baric, R. S., & Denison, M. R.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2019-12
- Volume
- 93
- Issue
- 24
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- OpenAlex
- W2979108578
- Cited by
- 337
- References
- 5
- FWCI
- 35.01
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. https://app.cochat.ai/papers/10.1128/jvi.01348-19
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- Agostini, M. L., Pruijssers, A. J., Chappell, J. D., Gribble, J., Lu, X., Andres, E. L., Bluemling, G. R., Lockwood, M. A., Sheahan, T. P., Sims, A. C., Natchus, M. G., Saindane, M., Kolykhalov, A. A., Painter, G. R., Baric, R. S., & Denison, M. R. (2019). Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. Journal of Virology. https://doi.org/10.1128/jvi.01348-19
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
