ArticlePLoS pathogens2025
Mutations in chikungunya virus nsP4 decrease viral fitness and sensitivity to the broad-spectrum antiviral 4'-Fluorouridine.
Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- A nanoluciferase-expressing attenuated CHIKV vaccine strain enables rapid and visual drug screeningJournal of virology · 2026Article
- Alphavirus replicase and regulatory RNA elements in host interactions and viral vector engineering.Journal of virology · 2026Review
- Identification and characterization of novel chikungunya virus polymerase inhibitors.Journal of virology · 2026Article
- Recent advances in antiviral drugs for Chikungunya virus (CHIKV): Targets, mechanisms, and development strategies.Acta pharmaceutica Sinica. B · 2026Review
- The oral nucleoside analogue inhibitor VV251 effectively inhibits coinfection by respiratory syncytial virus and influenza A virus.Journal of virology · 2026Article
- Pathogenesis of Chronic Arthritis Due to Chikungunya Virus and Advances in Vaccine Development.Viruses · 2026Review
- Efficacy of the nucleoside analog 4'-Fluorouridine against Nipah virus in the Syrian hamster model.PLoS pathogens · 2026Article
- A brief review of chikungunya fever: From molecular virology to countermeasures.Infectious medicine · 2026Review
- Impact of mutations affecting 4'-fluorouridine susceptibility on fitness and treatment outcomes for Venezuelan equine encephalitis virus.Journal of virology · 2026Article
- Chikungunya in 2025: Comprehensive Insights into Virology, Diagnostics, Vaccines, and Antiviral Therapies.Viruses · 2026Review
- Oral VV261 administration protects mice from lethal Crimean-Congo hemorrhagic fever virus challenge.Journal of virology · 2025Article
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- Alphavirus nsP2: A Multifunctional Regulator of Viral Replication and Promising Target for Anti-Alphavirus Therapies.Reviews in medical virology · 2025Review
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Authors and funding
13 authors.
Funding
Abstract
Chikungunya virus (CHIKV) is an arthritogenic alphavirus that has re-emerged to cause large outbreaks of human infections worldwide. There are currently no approved antivirals for treatment of CHIKV infection. Recently, we reported that the ribonucleoside analog 4'-fluorouridine (4'-FlU) is a highly potent inhibitor of CHIKV replication, and targets the viral nsP4 RNA dependent RNA polymerase. In mouse models, oral therapy with 4'-FlU diminished viral tissue burdens and virus-induced disease signs. To provide critical evidence for the potential of 4'-FlU as a CHIKV antiviral, here we selected for CHIKV variants with decreased 4'-FlU sensitivity, identifying two pairs of mutations in nsP2 and nsP4. The nsP4 mutations Q192L and C483Y were predominantly responsible for reduced sensitivity. These variants were still inhibited by higher concentrations of 4'-FlU, and the mutations did not change nsP4 fidelity or provide a virus fitness advantage in vitro or in vivo. Pathogenesis studies in mice showed that the nsP4-C483Y variant caused similar disease and viral tissue burden as WT CHIKV, while the nsP4-Q192L variant was strongly attenuated. Together these results support the potential of 4'-FlU to be an important antiviral against CHIKV.
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