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 Pharm Sin B. 2025 Aug;15(8):4156-4173. doi: 10.1016/j.apsb.2025.05.031.
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
  • 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.
  • 4. MOE Key Laboratory of Infectious Diseases Research in South China, Southern Medical University, Guangzhou 510515, China.
  • 5. State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
PMID: 40893672 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 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.

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