Rational design and synthesis of optimized glycoclusters for multivalent lectin-carbohydrate interactions: Influence of the linker arm

Samy Cecioni, Jean-Pierre Praly, Susan E. Matthews, Michaela Wimmerová, Anne Imberty, Sébastien Vidal

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)6250-6263
Number of pages14
JournalChemistry - A European Journal
Volume18
Issue number20
Early online date4 Apr 2012
DOIs
Publication statusPublished - 14 May 2012

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