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2014 Abstracts

The effect of residue 21 on drug resistance of the A/M2 proton channel of the influenza virus

Cameron Haas, Brigham Young University

Life Sciences

The influenza A virus contains a proton-selective ion channel, A/M2, through which acidification of the cell is induced. A/M2 is a homotetramer (consists of four identical helices) consisting of 97 residues and activated by low pH levels. Mutations in the amino acid sequences may induce resistance to channel inhibiting drugs. It is believed that residues 26, 27, 30, 31, and 34 are the major contributors of drug resistance, but other nearby residues may prove important as well. The A/California/04/2009 version of the influenza virus is sensitive to the drug AK-11, while its M2 channel is not. The A/Udorn/307/1972 with the S31N mutation M2 channel has been shown to have reduced sensitivity to amantadine compared to its wild type. While both contain a D (aspartic acid) at residue 21, A/Puerto Rico/8/1934 has a mutation from D to G (glycine). The A/Puerto Rico/8/1934 virus A/M2 contains mutations S31N and V27T and has shown sensitivity to the AK-11 drug, but the mechanism of inhibition of the A/M2 channel has not been verified. In these experiments we will be identifying sensitivity to AK11 of A/Udorn/307/1972 with the S31N mutation as well as inducing double mutations with S31N at residues 27 and 21 in the A/M2 from the virus and measure sensitivity by electrophysiological recordings in oocytes of Xenopus laevis. By doing so we may identify the role of these residues in drug resistance and the effects of these amino acid mutations, while verifying the A/M2 channel as the mechanism of acidification inhibition and drug sensitivity. We hypothesize that either D21G, V27T or both mutations causes drug sensitivity in M2 S31N, explaining the sensitivity of A/Puerto Rico/8/1934 to AK-11.