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Rational Design and Synthesis of Optimized Glycoclusters for Multivalent Lectin–Carbohydrate Interactions: Influence of the Linker Arm

Authors

  • Dr. Samy Cecioni,

    1. Institut de Chimie et Biochimie, Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France), Fax: (+33) 472-432-752
    2. Centre de Recherche sur les Macromolécules Végétales (CNRS) affiliated with Université Joseph Fourier, Grenoble and ICMG, BP 53, 38041 Grenoble (France)
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  • Dr. Jean-Pierre Praly,

    1. Institut de Chimie et Biochimie, Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France), Fax: (+33) 472-432-752
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  • Dr. Susan E. Matthews,

    1. School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ (UK)
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  • Dr. Michaela Wimmerová,

    1. Central European Institute of Technology, Masaryk University, 62500 Brno (Czech Republic)
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  • Dr. Anne Imberty,

    Corresponding author
    1. Centre de Recherche sur les Macromolécules Végétales (CNRS) affiliated with Université Joseph Fourier, Grenoble and ICMG, BP 53, 38041 Grenoble (France)
    • Centre de Recherche sur les Macromolécules Végétales (CNRS) affiliated with Université Joseph Fourier, Grenoble and ICMG, BP 53, 38041 Grenoble (France)
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  • Dr. Sébastien Vidal

    Corresponding author
    1. Institut de Chimie et Biochimie, Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France), Fax: (+33) 472-432-752
    • Institut de Chimie et Biochimie, Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France), Fax: (+33) 472-432-752
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Abstract

The design of multivalent glycoclusters requires the conjugation of biologically relevant carbohydrate epitopes functionalized with linker arms to multivalent core scaffolds. The multigram-scale syntheses of three structurally modified triethyleneglycol analogues that incorporate amide moiety(ies) and/or a phenyl ring offer convenient access to a series of carbohydrate probes with different water solubilities and rigidities. Evaluation of flexibility and determination of preferred conformations were performed by conformational analysis. Conjugation of the azido-functionalized carbohydrates with tetra-propargylated core scaffolds afforded a library of 18 tetravalent glycoclusters, in high yields, by CuI-catalyzed azide–alkyne cycloaddition (CuAAC). The compounds were evaluated for their ability to bind to PA-IL (the LecA lectin from the opportunistic pathogen Pseudomonas aeruginosa). Biochemical evaluation through inhibition of hemagglutination assays (HIA), enzyme-linked lectin assays (ELLA), surface plasmon resonance (SPR), and isothermal titration microcalorimetry (ITC) revealed improved and unprecedented affinities for one of the monovalent probes (Kd=5.8 μM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin.

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