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J Med Chem
. 2026 Feb 26.
doi: 10.1021/acs.jmedchem.5c03547. Online ahead of print.
Zanamivir-Amantadine Conjugate: A Dual-Action Agent with Broad-Spectrum Synergistic Antiviral Efficacy
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
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.
. 2026 Feb 26.
doi: 10.1021/acs.jmedchem.5c03547. Online ahead of print.
Zanamivir-Amantadine Conjugate: A Dual-Action Agent with Broad-Spectrum Synergistic Antiviral Efficacy
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
- PMID: 41744161
- DOI: 10.1021/acs.jmedchem.5c03547
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.