Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.

Autor: Arns S; The Centre for Drug Research and Development, Vancouver, BC, Canada., Balgi AD; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Shimizu Y; The Centre for Drug Research and Development, Vancouver, BC, Canada., Pfeifer TA; The Centre for Drug Research and Development, Vancouver, BC, Canada., Kumar N; The Centre for Drug Research and Development, Vancouver, BC, Canada., Shidmoossavee FS; The Centre for Drug Research and Development, Vancouver, BC, Canada., Sun S; The Centre for Drug Research and Development, Vancouver, BC, Canada., Tai SS; Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada., Agafitei O; Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada., Jaquith JB; The Centre for Drug Research and Development, Vancouver, BC, Canada., Bourque E; The Centre for Drug Research and Development, Vancouver, BC, Canada., Niikura M; Faculty of Heath Sciences, Simon Fraser University, Burnaby, BC, Canada., Roberge M; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address: michelr@mail.ubc.ca.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2016 Sep 14; Vol. 120, pp. 64-73. Date of Electronic Publication: 2016 May 07.
DOI: 10.1016/j.ejmech.2016.05.008
Abstrakt: 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.
(Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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