title: Rational design and synthesis of optimized glycoclusters for multivalent lectin-carbohydrate interactions: influence of the linker arm.
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 Cu(I)-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 (K(d)=5.8 μM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin.
authors.affiliation: 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.
authors.forename: Samy
authors.initials: S
authors.lastname: Cecioni
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Praly
authors.forename: Susan E
authors.initials: SE
authors.lastname: Matthews
authors.forename: Michaela
authors.initials: M
authors.lastname: Wimmerová
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
authors.forename: Sébastien
authors.initials: S
authors.lastname: Vidal
mesh_terms: D057930:Click Chemistry; D018360:Crystallography, X-Ray; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000737:chemistry; D006385:Hemagglutination Inhibition Tests; D037102:Lectins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006001:Glycoconjugates; D037102:Lectins; D008024:Ligands