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Theses

Conception de modèles de fibres amyloïdes et d'inhibiteurs de la fibrillogénèse

Abstract : Amyloid peptides and proteins are associated with several diseases named amyloidoses. These proteins, in conditions that are still unclear, fold into cross-β-sheet structures and form fibrils. In order to gain insight into the folding process, we have designed models of amyloid fibrils by the synthesis of polypeptidic edifices based on the sequence of the β amyloid peptide. They are made of two or four mutated, linear or cyclic, β-amyloid fragments covalently attached to a cyclic decapeptide scaffold. These polypeptidic edifices fold into cross-β-sheet structures and polymerize into protofilaments with diameters of 5-6 nm. Using molecular modelling, we have demonstrated that the folding in β strand-loop-β strand structure and a central hydrophobic core are required for the formation of the parallel cross β sheet structures. These edifices are promising models that will allow a better understanding of the amyloid fibril formation.
Among the therapeutic approaches in development to fight amyloidoses, the inhibition of the fibril formation has been widely investigated. In this work we have developed inhibitors of fibrillogenesis by the attachment of hydrophobic compounds on the cyclic decapeptide. The aim of this strategy is to create an important area of interaction with the amyloid β peptide and thus disturb its self-assembly process. We have shown by performing Aβ40 polymerization assays that these compounds are very efficient inhibitors which contrast with monomeric analogues. These results support the interest of this strategy to interfere with the amyloid fibril formation.
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https://tel.archives-ouvertes.fr/tel-00361444
Contributor : Myriam Ouberaï <>
Submitted on : Sunday, February 15, 2009 - 5:51:30 PM
Last modification on : Friday, November 6, 2020 - 4:10:18 AM
Long-term archiving on: : Tuesday, June 8, 2010 - 10:29:11 PM

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  • HAL Id : tel-00361444, version 1

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Myriam Ouberaï. Conception de modèles de fibres amyloïdes et d'inhibiteurs de la fibrillogénèse. Chimie. Université Joseph-Fourier - Grenoble I, 2008. Français. ⟨tel-00361444⟩

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