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

https://doi.org/10.1016/j.apsb.2025.05.031

This new article publication from Acta Pharmaceutica Sinica B, discusses how a novel C-3-substituted oleanolic acid benzyl amide derivative exhibits therapeutic potential against influenza A.

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. The authors of this article 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: Influenza A virus, RNA polymerase, Protein–protein interaction, Pentacyclic triterpenoids, Oleanolic acid amide derivatives, Drug-resistant strains, Inflammation, Toll-like receptor 4

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S221138352500365X-ga1_lrg.jpg   

A novel C-3-substituted oleanolic acid benzyl amide derivative, designated A5, inhibits the influenza A virus by disrupting the interaction between PA_C–PB1_N and prevents cytokine storms by targeting TLR4–MyD88–NF-κB signaling pathways.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 24.3

Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy) 

JIF without self-citation: 13.8

ISSN 2211-3835

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Kunyu Lu, Jianfu He, Chongjun Hong, Haowei Li, Jiaai Ruan, Jinshen Wang, Haoxing Yuan, Binhao Rong, Chan Yang, Gaopeng Song, Shuwen Liu, 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, Acta Pharmaceutica Sinica B, Volume 15, Issue 8, 2025, Pages 4156-4173, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.05.031