A novel C-3-substituted oleanolic acid benzyl amide derivative exhibits therapeutic potential against influenza A by targeting PA-PB1 interactions and modulating host macrophage inflammation.

The influenza A virus (IAV), renowned for its high contagiousness and potential to catalyze global pandemics, poses significant challenges due to the emergence of drug-resistant strains. Given the critical role of RNA polymerase in IAV replication, it stands out as a promising target for anti-IAV therapies. In this study, we identified a novel C-3-substituted oleanolic acid benzyl amide derivative, , as a potent inhibitor of the PA-PB1 polymerase subunit interaction, with an IC value of 0.96 ± 0.21 μmol/L. specifically targets the highly conserved PA domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains, including multidrug-resistant strains, with EC values ranging from 0.60 to 1.83 μmol/L. Notably, when combined with oseltamivir, exhibits synergistic effects both and . In a murine model, dose-dependent administration of leads to a significant reduction in IAV titers, resulting in a high survival rate among treated mice. Additionally, treatment inhibits virus-induced Toll-like receptor 4 activation, attenuates cytokine responses, and protects against IAV-induced inflammatory responses in macrophages. In summary, emerges as a novel inhibitor with high efficiency and broad-spectrum anti-influenza activity.