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  • Monovalent mannose-based DC-SIGN antagonists: targeting the hydrophobic groove of the receptor
    Tomašič, Tihomir ...
    Dendritic cell-specific, intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed specifically on dendritic cells. It is a primary site for recognition and ... binding of various pathogens and thus a promising therapeutic target for inhibition of pathogen entry and subsequent prevention of immune defense cell infection. We report the design and synthesis of D-mannose-based DC-SIGN antagonists bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties incorporated to target the hydrophobic groove of the receptor. The designed glycomimetics were evaluated by in vitro assay of the isolated DCSIGN extracellular domain for their ability to compete with HIV-1 gp120 for binding to the DC-SIGN carbohydrate recognition domain. Compounds 14d and 14e, that display IC50 values of 40 ŽM and 50 ŽM, are among the most potent monovalent DC-SIGN antagonists reported. The antagonistic effect of all the synthesized compounds was further evaluated by a one-point in vitro assay that measures DC adhesion. Compounds 14d, 14e, 18d, and 18e were shown to act as functional antagonists of DC-SIGN-mediated DC adhesion. The binding mode of 14d was also studied by molecular docking and molecular dynamics simulation, which revealed flexibility of 14d in the binding site and provides a basis for further optimization.
    Vir: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 75, 2014, str. 308-326)
    Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasle
    Leto - 2014
    Jezik - angleški
    COBISS.SI-ID - 3602033

    Povezava(-e):

    http://www.sciencedirect.com/science/article/pii/S0223523414000932#
    DOI

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