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

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.