ArticleJournal of virology2017
Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase.
Article in Journal of virology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Advances in Antiviral Drug Development Targeting Enteroviruses: From Viral Proteins to Host Factors.Viruses · 2026Review
- Impact of mutations affecting 4'-fluorouridine susceptibility on fitness and treatment outcomes for Venezuelan equine encephalitis virus.Journal of virology · 2026Article
- Virulence determinant of Senecavirus A: 3C protein functions as a protease to cleave viral polyprotein and host factors.Virulence · 2025Review
- Strategies and efforts in circumventing the emergence of antiviral resistance against conventional antivirals.npj antimicrobials and resistance · 2025Review
- Green synthesis of structural analogs of favipiravir.RSC advances · 2025Article
- Using reverse genetics tool for study of Senecavirus A: pros and cons.Frontiers in veterinary science · 2025Article
- Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2.Topics in current chemistry (Cham) · 2023Review
- RVG Peptide-Functionalized Favipiravir Nanoparticle Delivery System Facilitates Antiviral Therapy of Neurotropic Virus Infection in a Mouse Model.International journal of molecular sciences · 2023Article
- Exploring new antiviral targets for influenza and COVID-19: Mapping promising hot spots in viral RNA polymerases.Virology · 2023Article
- RNA-Dependent RNA Polymerase of the Second Human Pegivirus Exhibits a High-Fidelity Feature.Microbiology spectrum · 2022Article
- Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication.Viruses · 2022Review
- Task-driven knowledge graph filtering improves prioritizing drugs for repurposing.BMC bioinformatics · 2022Article
- Detailed Analyses of Molecular Interactions between Favipiravir and RNA Viruses In Silico.Viruses · 2022Article
- 5-Iodotubercidin inhibits SARS-CoV-2 RNA synthesis.Antiviral research · 2022Article
- Identification of Single Amino Acid Changes in the Rift Valley Fever Virus Polymerase Core Domain Contributing to Virus AttenuationFrontiers in cellular and infection microbiology · 2022Article
- DFT and MD simulation investigation of favipiravir as an emerging antiviral option against viral protease (3CLJournal of molecular structure · 2021Article
- Surface plasmon resonance approach to study drug interactions with SARS-CoV-2 RNA-dependent RNA polymerase highlights treatment potential of suramin.Journal of virological methods · 2021Article
- Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses.Molecular cell · 2021Article
- A novel mechanism of enhanced transcription activity and fidelity for influenza A viral RNA-dependent RNA polymerase.Nucleic acids research · 2021Article
- Cyanorona-20: The first potent anti-SARS-CoV-2 agent.International immunopharmacology · 2021Article
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11 authors.
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Abstract
Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis analysis at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme.
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