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Rational Design and Synthesis of Optimized Glycoclusters for Multivalent Lectin–Carbohydrate Interactions: Influence of the Linker Arm
Author(s) -
Cecioni Samy,
Praly JeanPierre,
Matthews Susan E.,
Wimmerová Michaela,
Imberty Anne,
Vidal Sébastien
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200010
Subject(s) - chemistry , linker , lectin , combinatorial chemistry , click chemistry , surface plasmon resonance , moiety , rational design , stereochemistry , biochemistry , nanotechnology , materials science , computer science , nanoparticle , operating system
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 μ M ) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin.