Matrix protein 2 (M2) or Influenza A virus matrix protein 2 (M2 or AM2 (for influenza A M2))

The influenza A matrix protein 2 (M2) is a 97-residue transmembrane proton channel that forms a tetrameric ion channel in the viral envelope, making it essential for influenza virus replication and a critical target for antiviral therapy. The channel selectively conducts protons across viral and cellular membranes through a mechanism dependent on His37 (pH sensor) and Trp41 (gate), enabling the acidification required for viral genome release during cell entry and proper viral assembly during exit. M2 was the first influenza antiviral target to be successfully exploited therapeutically, with amantadine and rimantadine (adamantane derivatives) showing potent activity by blocking the channel pore. However, high-frequency resistance mutations, particularly the S31N substitution, have rendered these drugs largely ineffective against contemporary influenza A strains, severely limiting their clinical utility. The M2 ectodomain is being evaluated as a potential universal influenza A vaccine candidate due to its high sequence conservation across viral strains. Structurally, M2 also plays critical roles in virus budding, membrane scission, and interaction with the matrix protein M1, making it a multifunctional viral protein beyond its well-characterized ion channel function.

Other names

ViroporinM2 proton channelM2 ion channelBM2 (influenza B functional ortholog)CM2 (influenza C functional ortholog)

Drugs like amantadine and rimantadine act by blocking proton conductance through the M2 ion channel pore. This inhibition prevents pH equilibration necessary for viral genome release and disassembly during cell entry and viral replication. Specifically, amantadine binds in the middle of the transmembrane pore (surrounded by Val27, Ala30, Ser31, and Gly34), while rimantadine binds to the lipid-facing outer surface of the pore.