Zanamivir-Amantadine Conjugate: A Dual-Action Agent with Broad-Spectrum Synergistic Antiviral Efficacy

  • J Med Chem. 2026 Mar 12;69(5):6063-6083. doi: 10.1021/acs.jmedchem.5c03547.
Yiming Wang  1  2  3 ,  Liwen Hua  1  2 ,  Honggao Duan  1  4  2 ,  Ruiwen Liu  1  2 ,  Mengyang Wang  1  2 ,  Peng Zhao  1  2  3 ,  Tao Yuan  1  2  3 ,  Yiping Zhong  1  2  3 ,  Rui Feng  1  2 ,  Xingxing Zhu  1  2  3 ,  Yongmin Zhang  5  6 ,  Demin Zhou  1  4  2  3 ,  Sulong Xiao  1  4  2  3  5
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Carbohydrate Intelligent Manufacture and Functional Applications, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. Peking University Ningbo Institute of Marine Medicines, Ningbo, Zhejiang 315832, China.
  • 3. Peking University-Yunnan Baiyao International Medical Research Center, Beijing 100191, China.
  • 4. China Southwest United Graduate School, Kunming 650092, China.
  • 5. Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, China.
  • 6. Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, Paris 75005, France.
PMID: 41744161 DOI: 10.1021/acs.jmedchem.5c03547
Abstract

Influenza A virus is a highly contagious respiratory pathogen, and its rapid and continuous adaptive mutations for immune escape have limited the efficacy of existing vaccines and Antiviral drugs. Here, we report a multimechanism anti-influenza platform based on the conjugation of zanamivir (ZMV) with amantadine (Aman). Aman acts as a hydrophobic tag that promotes the degradation of neuraminidase and concurrently enhances the physicochemical properties of ZMV, leading to improved membrane permeability and a significantly prolonged half-life. Meanwhile, the ZMV moiety counteracts Aman-induced cytotoxic Autophagy. The resulting conjugate, compound 7j, exhibits potent activity against a wide range of neuraminidase and M2 ion channel mutations. Notably, a single intravenous dose of 7j fully protected mice from a lethal H1N1 challenge. Our work demonstrates that the rational fusion of ZMV and Aman achieves synergistic multimechanistic Antiviral activity with enhanced efficacy and safety, offering a new strategy for the development of next-generation anti-influenza drugs.

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