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    Flipping in the pore: Discovery of dual inhibitors that bind in different orientations to the wild-type versus the amantadine-resistant s31n mutant of the influenza a virus m2 proton channel

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    Flipping in the pore discovery ...
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    Genre
    Journal Article
    Date
    2014-12-31
    Author
    Wu, Y
    Canturk, B
    Jo, H
    Ma, C
    Gianti, E
    Klein, ML
    Pinto, LH
    Lamb, RA
    Fiorin, G
    Wang, J
    Degrado, WF
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    Subject
    Amantadine
    Animals
    Dogs
    Drug Discovery
    Drug Resistance, Viral
    Influenza A virus
    Madin Darby Canine Kidney Cells
    Molecular Dynamics Simulation
    Mutation
    Porosity
    Protein Binding
    Protein Conformation
    Proton Pump Inhibitors
    Proton Pumps
    Structure-Activity Relationship
    Thiophenes
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5278
    
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    DOI
    10.1021/ja508461m
    Abstract
    © 2014 American Chemical Society. Influenza virus infections lead to numerous deaths and millions of hospitalizations each year. One challenge facing anti-influenza drug development is the heterogeneity of the circulating influenza viruses, which comprise several strains with variable susceptibility to antiviral drugs. For example, the wild-type (WT) influenza A viruses, such as the seasonal H1N1, tend to be sensitive to antiviral drugs, amantadine and rimantadine, while the S31N mutant viruses, such as the pandemic 2009 H1N1 (H1N1pdm09) and seasonal H3N2, are resistant to this class of drugs. Thus, drugs targeting both WT and the S31N mutant are highly desired. We report our design of a novel class of dual inhibitors along with their ion channel blockage and antiviral activities. The potency of the most active compound 11 in inhibiting WT and the S31N mutant influenza viruses is comparable with that of amantadine in inhibiting WT influenza virus. Solution NMR studies and molecular dynamics (MD) simulations of drug-M2 interactions supported our design hypothesis: namely, the dual inhibitor binds in the WT M2 channel with an aromatic group facing down toward the C-terminus, while the same drug binds in the S31N M2 channel with its aromatic group facing up toward the N-terminus. The flip-flop mode of drug binding correlates with the structure-activity relationship (SAR) and has paved the way for the next round of rational design of broad-spectrum antiviral drugs.
    Citation to related work
    American Chemical Society (ACS)
    Has part
    Journal of the American Chemical Society
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5260
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