title: Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.
abstract: The development of treatments for influenza that inhibit the M2 proton channel without being susceptible to the widespread resistance mechanisms associated with the adamantanes is an ongoing challenge. Using a yeast high-throughput yeast growth restoration assay designed to identify M2 channel inhibitors, a single screening hit was uncovered. This compound (3), whose structure was incorrectly identified in the literature, is an inhibitor with similar potency to amantadine against WT M2. A library of derivatives of 3 was prepared and activity against WT M2 and the two principal mutant strains (V27A and S31N) was assessed in the yeast assay. The best compounds were further evaluated in an antiviral plaque reduction assay using engineered WT, V27A and S31N M2 influenza A strains with otherwise identical genetic background. Compound 63 was found to inhibit all three virus strains in this cell based antiviral assay at micromolar concentrations, possibly through a mechanism other than M2 inhibition.
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Arns
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Aruna D
authors.initials: AD
authors.lastname: Balgi
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Pfeifer
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Nag
authors.initials: N
authors.lastname: Kumar
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Fahimeh S
authors.initials: FS
authors.lastname: Shidmoossavee
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sun
authors.affiliation: Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Sheldon S-H
authors.initials: SS
authors.lastname: Tai
authors.affiliation: Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Agafitei
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Jaquith
authors.affiliation: The Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Elyse
authors.initials: E
authors.lastname: Bourque
authors.affiliation: Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Niikura
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address: michelr@mail.ubc.ca.
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy; D009154:Mutation; D011522:Protons; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D011522:Protons; D054852:Small Molecule Libraries; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Antiviral; Influenza; M2; Spirothiazamenthane; Yeast