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 pol...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 IC_(50) value of 0.96±0.21μmol/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 EC_(50) values ranging from 0.60 to 1.83μmol/L.Notably,when combined with oseltamivir,A5 exhibits synergistic effects both in vitro and in vivo.In a murine model,dosedependent 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.展开更多
基金supported by the Major Scientific and Technological Projects of Guangdong Province(No.2023B1111050008,China)Science and Technology Innovation Project of Guangdong Provincial Drug Administration(No.2022ZDZ08,China)+3 种基金Post Scientist Fund awarded by Chinese Academy of Traditional Chinese Medicine(No.ZZ13-035-02,China)to Shuwen LiuThe-National Natural Science Foundation of China(No.82073722)the Guangdong Basic and Applied Basic Research Foundation(No.2025A1515010495,China)to Gaopeng SongRegional joint foundation of basic and applied basic research in guangdong province(No.2023A1515111165,China)to Chan Yang.
文摘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 IC_(50) value of 0.96±0.21μmol/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 EC_(50) values ranging from 0.60 to 1.83μmol/L.Notably,when combined with oseltamivir,A5 exhibits synergistic effects both in vitro and in vivo.In a murine model,dosedependent 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.
