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  • Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles

    Author(s)
    Mohan, Sankar
    McAtamney, Sarah
    Haselhorst, Thomas
    von Itzstein, Mark
    Pinto, Brian Mario
    Griffith University Author(s)
    von Itzstein, Mark
    Haselhorst, Thomas E.
    Pinto, Mario M.
    Year published
    2010
    Metadata
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    Abstract
    We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with Ki values in the 10-5-10-8 M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with Ki values of 1.5 נ10-9 and 4.6 נ10-10 M, respectively. The most active inhibitor of the N1 enzyme in the ...
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    We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with Ki values in the 10-5-10-8 M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with Ki values of 1.5 נ10-9 and 4.6 נ10-10 M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (Ki = 2.6 占vs 0.07 卩 of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.
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    Journal Title
    Journal of Medicinal Chemistry
    Volume
    53
    Issue
    20
    DOI
    https://doi.org/10.1021/jm100822f
    Copyright Statement
    Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
    Subject
    Medicinal and biomolecular chemistry
    Medicinal and biomolecular chemistry not elsewhere classified
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/35815
    Collection
    • Journal articles

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