Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene glycoconjugates

Cecioni, Samy, Lalor, Ruth, Blanchard, Bertrand, Praly, Jean-Pierre, Imberty, Anne, Matthews, Susan E. ORCID: and Vidal, Sebastien (2009) Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene glycoconjugates. Chemistry - A European Journal, 15 (47). pp. 13232-13240. ISSN 0947-6539

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A family of seven topologically isomeric calix[4]arene glycoconjugates was prepared through the synthesis of a series of alkyne-derivatised calix[4]arene precursors that are suitable for the attachment of sugar moieties by microwave-assisted copper(I)-catalysed azide–alkyne cycloaddition (CuAAC). The glycoconjugates thus synthesised comprised one mono-functionalised derivative, two 1,2- or 1,3-divalent regioisomers, one trivalent and three tetravalent topoisomers in the cone, partial cone or 1,3-alternate conformations. The designed glycoconjugates were evaluated as ligands for the galactose-binding lectin PA-IL from the opportunistic bacterium Pseudomonas aeruginosa, a major causative agent of lung infections in cystic fibrosis patients. Binding affinities were determined by isothermal titration calorimetry (ITC), and the interaction with the lectin was shown to be strongly dependant on both the valence and the topology. Whereas the trivalent conjugate displayed enhanced affinity when compared to a monosaccharide model, the tetravalent conjugates are to-date the highest-affinity ligands measured by ITC. The topologies presenting carbohydrates on both faces of calixarene are the most potent ones with dissociation constants of approximately 200 nM. Molecular modelling suggests that such a multivalent molecule can efficiently chelate two of the binding sites of the tetrameric lectin; this explains the 800-fold increase of affinity achieved by the tetravalent molecule. Surface plasmon resonance (SPR) experiments confirmed that this glycoconjugate is the strongest inhibitor for binding of PA-IL to galactosylated surfaces for potential applications as an anti-adhesive agent.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Depositing User: Rachel Smith
Date Deposited: 16 Mar 2011 16:16
Last Modified: 06 Jan 2023 09:32
DOI: 10.1002/chem.200901799

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