title: Quantitative analysis of influenza M2 channel blockers.
abstract: The influenza M2 H(+) channel enables the concomitant acidification of the viral lumen upon endosomic internalization. This process is critical to the viral infectivity cycle, demonstrated by the fact that M2 is one of only two targets for anti-flu agents. However, aminoadamantyls that block the M2 channel are of limited therapeutic use due to the emergence of resistance mutations in the protein. Herein, using an assay that involves expression of the protein in Escherichia coli with resultant growth retardation, we present quantitative measurements of channel blocker interactions. Comparison of detailed K(s) measurements of different drugs for several influenza channels, shows that the swine flu M2 exhibits the highest resistance to aminoadamantyls of any channel known to date. From the perspective of the blocker, we show that rimantadine is consistently a better blocker of M2 than amantadine. Taken together, such detailed and quantitative analyses provide insight into the mechanism of this important and pharmaceutically relevant channel blocker system.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem, 91904, Israel.
authors.forename: Peleg
authors.initials: P
authors.lastname: Astrahan
authors.forename: Ravenna
authors.initials: R
authors.lastname: Flitman-Tene
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry; D015153:Blotting, Western; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012299:Rimantadine / Q000494:pharmacology; D013997:Time Factors; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins