M2 protein

Pinto EH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel activity. Cell 69 517-528... 

Budding and release of progeny virus. B. Replicative cycle of an influenza virus, an example of an RNA virus. 1. Attachment. 2. Endocytosis. 3. Influx of H+ through M2 protein. 4. Fusion of the viral envelope with the endosomes membrane, dissociation of the RNP complex, and entry of viral RNA into the nucleus. 5. Synthesis of viral mRNA by viral RNA polymerase. 6. Translation of viral mRNA by host cell s ribosomes. 7. Replication of viral RNA, using viral RNA polymerase, via cRNA replicative form. 8. Assembly of virus particles, and 9. Budding and release of progeny virus. 

Their mechanism of action involves inhibition of the viral M2 protein, an integral membrane protein that acts as a H channel Blockade of the M2 protein prevents the acid-mediated dissociation of the ribonucleoprotein complex that occurs early in replication. In certain strains, the pH changes that result from M2 inhibition alter the conformation of hemagglutinin, hence inhibit viral assembly. 

Viral resistance develops rapidly in approximately 30% of individuals treated with amantadine or rimantadine. Resistant viruses are associated with the failure of drug prophylaxis in close contacts of infected individuals who have been treated with these antiviral agents. Mutation in the transmembrane domain of the M2 protein is the most frequent cause of resistance to amantadine and rimantadine. 

Mechanism of Action A dopaminergic agonist that blocks the uncoating of influenza A virus, preventing penetration into the host and inhibiting M2 protein in the assembly of progeny virions. Amantadine also blocks the reuptake of dopamine into presyn-aptic neurons and causes direct stimulation of postsynaptic receptors. Therapeutic Effect Antiviral and antiparkinsonian activity. 

The primary target for both agents is the M2 protein within the viral membrane this target incurs both specificity against influenza A (since influenza B contains a different protein in its membrane) and a mutation-prone site, causing the rapid development of resistance in up to 50% of treated... 

Amantadine Blockage of the M2 protein ion channel and its ability to modulate intracellular pH influenza A 10-30... 

Figure 1.28 Experimental (solid lines) and simulated (dashed lines) spin-echo spectra of 6F-Trp41-M2TMD at 6.5 kHz MAS at pH 5.3 (a) and pH 8.0 (b). Side-chain conformations (bottom view) of Trp41 (blue) and His37 (green) in the TM channel structure of the homo-tetrameric M2 protein are shown to the right side of the spectra. At pH 8.0, the structural parameters implicate an inactivated state, while at pH 5.3 the tryptophan conformation represents the activated state. See color plate 1.28.

The transmembrane portion of the M2 protein from the influenza A virus has been studied in hydrated DMPC lipid bilayers with solid-state NMR.209 Orientational constraints are obtained from the isotopically labeled peptide samples mechanically aligned between thin glass plates. I5N chemical shifts from single-site labeled samples constrain the molecular frame with respect to... 

MECHANISMS OF ACTION AND RESISTANCE Amantadine and rimantadine inhibit an early step in viral replication, probably viral uncoating for some strains, they also have an effect on a late step in viral assembly probably mediated through altering hemagglutinin processing. The primary locus of action is the influenza A virus M2 protein, an integral membrane protein that functions as an ion channel. 

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