Computational analysis reveals the mechanism of favipiravir against influenza A virus

Authors: Khaled M. Mekkawy, Fatma Abdalla, Mohammed A. Abd El-Mobdy, Abdou Nagy, Bader Y. Alhatlani, and Ahmed A. H. Ali

Ger. J. Vet. Res 2025. vol. 5, Iss. 4 pp:118-131
Doi: https://doi.org/10.51585/gjvr.2025.4.0167

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Abstract:

Current influenza antivirals are often ineffective and prone to resistance, particularly in severe infections. Therefore, new antiviral drugs should be developed and evaluated for resistance. Favipiravir is a broad-spectrum antiviral with proven efficacy against influenza. Its mechanism of action is primarily attributed to inhibition of viral RNA-dependent RNA polymerase (RdRp), coupled with its high barrier to resistance. However, the exact way in which favipiravir interferes with viral replication and affects host enzymes remains unknown. To investigate this issue, we performed computational analysis to examine how favipiravir interacts with the PB1 subunit of influenza A RNA-dependent RNA polymerase. We used X-ray crystallography and cryo-EM structures, along with docking studies, to evaluate binding dynamics. The results indicate that the anti-influenza efficacy of favipiravir relies on the conformational state of the RdRp during both transcription and replication. Furthermore, resistance to favipiravir is infrequent, as the drug acts on critical polymerase basic protein 1 (PB1) residues required for polymerase functionality and structural integrity. Further research is required to validate the in-silico-predicted mechanism of action of favipiravir.

Keywords:

Antiviral, Favipiravir, Influenza A virus, Influenza, Polymerase

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