Background: M2 channel protein of influenza A virus is one of the specific targets for the
anti-influenza drugs amantadine and rimantadine. These drugs have lost their efficacy because of the
mutations in their drug interaction sites. Large-scale analysis of these influenza surface proteins may
give better elucidation for understanding the evolution of the proteins toward the drug resistant
Objective: The current investigation aimed to understand the evolutionary lineage and to enlighten the
mechanism of drug resistance in newly emerging strains.
Method: Combined sequence, secondary structural, evolutionary conservation, and phylogenetic
analyses were carried out with 2010 influenza A M2 channel protein sequences.
Results: The structural information provides enough details for understanding the drug resistance in the
target proteins. Herein, secondary structural analysis of M2 sequences predicted the variation only in the
drug binding region. The rate of mutation in S31N is high in swine/H3N2 than in human/H1N1,
human/H3N2, swine/H1N1, and avian/H5N influenza A viruses. This confirms that antigenic drift does
not affect the functional mechanism of the protein. Also, it reports that the avian influenza virus is the
source for the M2 gene segment and has transferred from the avian to human and swine. Our findings
show that the M2 gene segment has interchanged between swine and human.
Conclusion: This study proves that rapid mutation and frequent reassortment play a major role in drug
resistant strains. Phylogenetic and secondary structural analysis confirms the existence of a genetic
lineage between avian, swine, and human influenza A viruses.