Repurposing of the nucleoside analogs for influenza

Abstract

Influenza viruses remain a global health concern prompting the search for new antivirals. Drug repurposing offers an efficient approach to identify potential therapeutics. This study repurposed 35 FDA-approved nucleoside analogs, screening them against influenza H1N1. Seven compounds exhibited significant antiviral activity, with cytidine analogs Gemcitabine (IC₅₀ = 0.64 ± 0.21 µM) and 5-Azacytidine (IC₅₀ = 3.42 ± 0.38 µM) showing the strongest inhibition. Molecular dynamics simulations showed that key binding site residues (Arg45, Lys229, Arg239, Lys308, Lys480) and a magnesium ion are crucial for drug binding. Stable hydrogen bonds between active analogs and specific residues (Arg239, Thr307, Asn310), along with significant interactions with RNA complementary bases, are associated with antiviral activity. These findings offer structural insights into polymerase inhibition and provide a foundation for future drug design and monitoring of resistance development. © 2025 The Authors