Influenza A virus matrix protein 2 proton channel (M2)

The M2 proton channel is a small, homotetrameric integral membrane protein found in the viral envelope of the influenza A virus, with a closely related but sequence-divergent counterpart in influenza B[1][3][7]. It forms a highly selective, pH-activated proton channel responsible for transporting protons from acidified endosomes into the viral interior during cell entry, a process essential for viral uncoating and initiation of infection[1][3][7][9]. The channel is also involved in modulating pH in the trans-Golgi during viral maturation and facilitating virus particle release[1][7]. Structurally, the channel is formed by four transmembrane helices, with key residues such as histidine 37 acting as the proton sensor and tryptophan 41 as the gate[6][7][9]. The activity of the M2 channel is blocked by the adamantane drugs amantadine and rimantadine, but high rates of resistance (e.g., S31N mutation) have limited their use[7][10]. The M2 protein remains a validated antiviral drug target, especially in the development of next-generation inhibitors for influenza therapeutics.

Other names

M2 proton channelInfluenza A M2 protein (AM2)Influenza B M2 protein (BM2)M2 ion channel

Channel blockade (e.g., amantadine/rimantadine bind within the pore, blocking proton conductance) Inhibition of pH regulation within virion, thereby impeding viral uncoating and replication