Monovalent mannose-based DC-SIGN antagonists: Targeting the hydrophobic groove of the receptor

• A focused library of diaryl-based d-mannosides was designed and synthesized.
• Competition of compounds with HIV-1 gp120 for binding to DC-SIGN ECD was evaluated.
• DC-SIGN-mediated DC adhesion and cytotoxicity of identified antagonists was tested.
• Compound 14d was found to be the most potent DC-SIGN antagonist with an IC50 of 40 μM.
• Binding mode of 14d to DC-SIGN CRD was studied by docking and molecular dynamics.

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 DC-SIGN 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 μM and 50 μM, 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.

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