Influenza A virus matrix protein 2 (M2) (M2)

The Influenza A virus matrix protein 2 (M2) is a small, 97-amino acid homotetrameric integral membrane protein that functions as a pH-gated, proton-selective ion channel (UniProt P06821). It is essential for the viral life cycle, particularly during the uncoating stage where it allows protons from the acidified endosome to enter the virion interior (PubMed: 20111058). This influx of protons triggers the dissociation of the viral ribonucleoprotein (vRNP) from the Matrix protein 1 (M1), enabling the release of the viral genome into the host cell cytoplasm (StatPearls: NBK541092). M2 also plays a critical role during viral assembly and budding, and it helps maintain the pH gradient in the Golgi apparatus to prevent premature conformational changes in the hemagglutinin protein (PubMed: 16254364). Historically, the M2 channel has been the primary target for adamantane-class antivirals like amantadine and rimantadine, which block the channel pore to inhibit viral replication (PubChem CID 2130). However, the clinical utility of these drugs is currently severely limited due to the near-universal prevalence of resistance-conferring mutations, such as the S31N substitution, in circulating seasonal and pandemic influenza strains (CDC: Influenza Antiviral Drug Resistance).

Other names

M2 proteinMatrix protein 2M2 ion channelProton channel M2Viroporin M2

Adamantane-class drugs, such as amantadine and rimantadine, function by binding to the transmembrane pore of the M2 tetramer, thereby physically obstructing the passage of protons (PubMed: 20111058). This blockage prevents the acidification of the virion interior during endocytosis, which is required for the dissociation of the viral ribonucleoprotein (vRNP) from the M1 matrix protein, effectively halting the uncoating process and preventing the viral genome from entering the host cell nucleus (StatPearls: NBK541092).