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

Cecioni, Samy, Praly, Jean-Pierre, Matthews, Susan E. ORCID: https://orcid.org/0000-0001-8821-0851, Wimmerová, Michaela, Imberty, Anne and Vidal, Sébastien (2012) Rational design and synthesis of optimized glycoclusters for multivalent lectin-carbohydrate interactions: Influence of the linker arm. Chemistry - A European Journal, 18 (20). pp. 6250-6263. ISSN 1521-3765

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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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User:	Sophie Buckingham
Date Deposited:	03 Mar 2013 22:13
Last Modified:	08 May 2024 00:39
URI:	https://ueaeprints.uea.ac.uk/id/eprint/41601
DOI:	10.1002/chem.201200010

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