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.
10.1016/j.apsb.2025.05.031
- Author:
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
;
Gaopeng SONG
2
;
Shuwen LIU
1
Author Information
1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory of Drug Metabolism Research and Evaluation, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
2. Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
3. The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China.
- Publication Type:Journal Article
- Keywords:
Drug-resistant strains;
Inflammation;
Influenza A virus;
Oleanolic acid amide derivatives;
Pentacyclic triterpenoids;
Protein–protein interaction;
RNA polymerase;
Toll-like receptor 4
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4156-4173
- CountryChina
- Language:English
-
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 PAC-PB1N polymerase subunit interaction, with an IC50 value of 0.96 ± 0.21 μmol/L. A5 specifically targets the highly conserved PAC 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.
