Acta Pharm Sin B . 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

[tetano]

Acta Pharm Sin B


. 2025 Aug;15(8):4322-4323.
doi: 10.1016/j.apsb.2025.07.033. Epub 2025 Aug 19. A5-A dual-target antiviral compound that rewrites the rules of influenza therapy

Shibo Jiang ¹



Affiliations

• PMID: 40893695
• PMCID: PMC12399219
• DOI: 10.1016/j.apsb.2025.07.033

No abstract available Keywords: Dual-target therapy; Influenza; RNA-dependent RNA polymerase.

[tetano]

Acta Pharm Sin B


. 2025 Aug;15(8):4156-4173.
doi: 10.1016/j.apsb.2025.05.031. Epub 2025 May 29. 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

Kunyu Lu ¹ , Jianfu He ¹ , Chongjun Hong ² , Haowei Li ¹ , Jiaai Ruan ² , Jinshen Wang ¹ , Haoxing Yuan ¹ , Binhao Rong ¹ , Chan Yang ^{3 4} , Gaopeng Song ² , Shuwen Liu ^{1 5 3 4}



Affiliations

• PMID: 40893672
• PMCID: PMC12399203
• DOI: 10.1016/j.apsb.2025.05.031

Abstract

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, A5, as a potent inhibitor of the PA_C-PB1_N polymerase subunit interaction, with an IC₅₀ value of 0.96 ± 0.21 μmol/L. A5 specifically targets the highly conserved PA_C domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains, including multidrug-resistant strains, with EC₅₀ values ranging from 0.60 to 1.83 μmol/L. Notably, when combined with oseltamivir, A5 exhibits synergistic effects both in vitro and in vivo. In a murine model, dose-dependent administration of A5 leads to a significant reduction in IAV titers, resulting in a high survival rate among treated mice. Additionally, A5 treatment inhibits virus-induced Toll-like receptor 4 activation, attenuates cytokine responses, and protects against IAV-induced inflammatory responses in macrophages. In summary, A5 emerges as a novel inhibitor with high efficiency and broad-spectrum anti-influenza activity.

Keywords: Drug-resistant strains; Inflammation; Influenza A virus; Oleanolic acid amide derivatives; Pentacyclic triterpenoids; Protein–protein interaction; RNA polymerase; Toll-like receptor 4.