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

作者：Yiming Wang, Liwen Hua, Honggao Duan, Ruiwen Liu, Mengyang Wang, P Zhao, Tao Yuan, Yiping Zhong, Rui Feng, Xingxing Zhu, Y. Zhang, Demin Zhou, S. Y. Xiao · 发表于：Journal of Medicinal Chemistry · 年份：2026 · DOI：10.1021/acs.jmedchem.5c03547 · 研究领域：Influenza Virus Research Studies、Respiratory viral infections research、Mosquito-borne diseases and control

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.