tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Jianfu He[SUP] 1 [/SUP], Chongjun Hong[SUP] 2 [/SUP], Haowei Li[SUP] 1 [/SUP], Jiaai Ruan[SUP] 2 [/SUP], Jinshen Wang[SUP] 1 [/SUP], Haoxing Yuan[SUP] 1 [/SUP], Binhao Rong[SUP] 1 [/SUP], Chan Yang[SUP] 3 4 [/SUP], Gaopeng Song[SUP] 2 [/SUP], Shuwen Liu[SUP] 1 5 3 4 [/SUP]
Affiliations
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[SUB]C[/SUB]-PB1[SUB]N[/SUB] polymerase subunit interaction, with an IC[SUB]50[/SUB] value of 0.96 ± 0.21 μmol/L. A5 specifically targets the highly conserved PA[SUB]C[/SUB] domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains, including multidrug-resistant strains, with EC[SUB]50[/SUB] 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.
. 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[SUP] 1 [/SUP], Jianfu He[SUP] 1 [/SUP], Chongjun Hong[SUP] 2 [/SUP], Haowei Li[SUP] 1 [/SUP], Jiaai Ruan[SUP] 2 [/SUP], Jinshen Wang[SUP] 1 [/SUP], Haoxing Yuan[SUP] 1 [/SUP], Binhao Rong[SUP] 1 [/SUP], Chan Yang[SUP] 3 4 [/SUP], Gaopeng Song[SUP] 2 [/SUP], Shuwen Liu[SUP] 1 5 3 4 [/SUP]
Affiliations
- PMID: 40893672
- PMCID: PMC12399203
- DOI: 10.1016/j.apsb.2025.05.031
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[SUB]C[/SUB]-PB1[SUB]N[/SUB] polymerase subunit interaction, with an IC[SUB]50[/SUB] value of 0.96 ± 0.21 μmol/L. A5 specifically targets the highly conserved PA[SUB]C[/SUB] domain and demonstrates remarkable efficacy against both laboratory-adapted and clinically isolated IAV strains, including multidrug-resistant strains, with EC[SUB]50[/SUB] 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.