Influenza virus matrix protein 2 (M2 protein)

The **Influenza virus matrix protein 2 (M2 protein)** is a small, integral membrane proton channel (viroporin) found in the viral envelope of the influenza A virus. It is essential for the viral life cycle, mediating the influx of protons into the viral particle during entry, which facilitates release of the viral ribonucleoprotein complex into the host cytoplasm—a key step in viral uncoating and infection[1][3]. The M2 protein is a homotetrameric channel (four identical subunits) that forms a highly selective, low-conductance, pH-activated proton channel, with histidine 37 functioning as the pH sensor and tryptophan 41 as the gate[1][2][3]. During the early stage of infection, the M2 channel allows protons from the acidified endosome to enter the virion, promoting dissociation of the matrix protein from the viral RNA. In the late phase of replication, M2 balances pH within the trans-Golgi network, preventing premature conformational changes of other viral proteins (e.g., hemagglutinin)[1][2][3]. The protein also plays a key role in virion budding and membrane scission[2]. **The M2 ion channel is a validated antiviral target.** Drugs such as amantadine and rimantadine inhibit the channel and block viral replication, but widespread resistance—especially the S31N mutation—significantly limits their clinical utility[1][2][3]. The M2 protein is distinctive for its minimalist channel structure, comprising ~97 amino acids with a short N-terminal extracellular domain, single transmembrane helix, and C-terminal cytoplasmic tail that participates in virus assembly and budding[1][2][3]. Alternative forms with similar function exist in influenza B (BM2) and C (CM2) viruses. No established biomarkers exist for patient selection or monitoring efficacy for M2-targeting agents. The major safety concern is drug resistance and the limited spectrum of existing drugs, as well as potential off-target effects of ion channel inhibitors[1][2][3].

Other names

M2 proton channelM2 ion channelMatrix-2 proteinAM2 protein (for Influenza A)Influenza A virus M2 protein

Channel blockers (amantadine and rimantadine block proton conduction through the M2 channel, inhibiting viral uncoating and replication)