Selective Targeting of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin (DC-SIGN) with Mannose-Based Glycomimetics: Synthesis and Interaction Studies of Bis(benzylamide) Derivatives of a Pseudomannobioside

Authors

  • Norbert Varga,

    1. Universita' degli Studi di Milano, Dipartimento di Chimica via Golgi 19, 20133 Milano (Italy)
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    • These authors contributed equally to this work.

  • Ieva Sutkeviciute,

    1. Université Grenoble I, Institut de Biologie Structurale, 41 rue Jules Horowitz, Grenoble, 38027 (France)
    2. CNRS, UMR 5075, Grenoble, 38000 (France)
    3. CEA, DSV, Grenoble, 38000 (France)
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    • These authors contributed equally to this work.

  • Cinzia Guzzi,

    1. Glycosystems Laboratory, Instituto de Investigaciones, Químicas (IIQ), CSIC - Universidad de Sevilla, Américo Vespucio 49, 41092 Sevilla (Spain)
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  • John McGeagh,

    1. Anterio Consult&Research GmbH, Augustaanlage 23, 68165 Mannheim (Germany)
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  • Isabelle Petit-Haertlein,

    1. Université Grenoble I, Institut de Biologie Structurale, 41 rue Jules Horowitz, Grenoble, 38027 (France)
    2. CNRS, UMR 5075, Grenoble, 38000 (France)
    3. CEA, DSV, Grenoble, 38000 (France)
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  • Serena Gugliotta,

    1. Universita' degli Studi di Milano, Dipartimento di Chimica via Golgi 19, 20133 Milano (Italy)
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  • Jörg Weiser,

    1. Anterio Consult&Research GmbH, Augustaanlage 23, 68165 Mannheim (Germany)
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  • Jesús Angulo,

    1. Glycosystems Laboratory, Instituto de Investigaciones, Químicas (IIQ), CSIC - Universidad de Sevilla, Américo Vespucio 49, 41092 Sevilla (Spain)
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  • Franck Fieschi,

    1. Université Grenoble I, Institut de Biologie Structurale, 41 rue Jules Horowitz, Grenoble, 38027 (France)
    2. CNRS, UMR 5075, Grenoble, 38000 (France)
    3. Institut Universitaire de France, 103 boulevard Saint-Michel 75005 Paris (France)
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  • Anna Bernardi

    Corresponding author
    1. Universita' degli Studi di Milano, Dipartimento di Chimica via Golgi 19, 20133 Milano (Italy)
    • Universita' degli Studi di Milano, Dipartimento di Chimica via Golgi 19, 20133 Milano (Italy)
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Abstract

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3–4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN.

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