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Approche multivalente des interactions saccharides - lectines : synthèse de glycoclusters et analyse de la reconnaissance biomoléculaire

Abstract : Following Fischer's “lock-key“ concept, non-covalent interactions between a ligand and its receptor is one of the most fundamental process of any biological system. The presence of multiple keys and locks at the surface of many biomolecules leads to multivalent interactions. Lectins are appropriate partners for the study of multivalent interactions with multivalent glycoconjugates since lectins are generally organized as homomultimers. Association of ligands and receptors can occur through several mechanisms leading to distinct thermodynamic and kinetic patterns. Thermodynamic and kinetic parameters often rationalize the impressive affinity improvement observed in the context of multivalent interactions. Small and low valency multivalent ligands provide a neat organization of carbohydrates through a single well-defined structure. These glycoclusters are appropriate probes for studying the influence of the overall topology on the interaction. Glycocluster synthesis was optimized according to a convergent strategy consisting of a glycosidation reaction followed by multiple CuAAC couplings. This strategy yielded a library of glycoclusters based on conformers of calix[4]arenes, linear and cyclic peptoids and porphyrins scaffolds. Glycoclusters were evaluated thanks to a combination of four biochemical techniques (HIA, ELLA, SPR, ITC) mainly versus PA-IL, a tetrameric lectin from Pseudomonas aeruginosa. Further investigations of these ligands were performed with a plant lectin from Erythrina cristagalli and with human galectin-1. Second generation glycoclusters were prepared in order to optimize enthalpic and entropic contributions to the interaction. Results indicate that a slight modification of the glycocluster topology could induce different mechanisms. The design of glycoclusters with stiffened linkers highlights unexpected entropic patterns. Molecular modeling of these linkers provided rationalization of these entropic patterns on the basis of Boltzmann distribution. This work present glycoclusters with an unprecedented affinity for PA-IL. The best first generation glycocluster confirmed promising therapeutic potentialities in vivo.
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  • HAL Id : tel-00732336, version 1

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Samy Cecioni. Approche multivalente des interactions saccharides - lectines : synthèse de glycoclusters et analyse de la reconnaissance biomoléculaire. Autre. Université Claude Bernard - Lyon I, 2010. Français. ⟨NNT : 2010LYO10278⟩. ⟨tel-00732336⟩

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