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Rôle de la Caspase-2 au cours des processus neurodégénératifs associés au vieillissement. Conception rationnelle d’inhibiteurs sélectifs et évaluation sur des modèles biologique

Abstract : Caspase-2 (CASP-2) is unique among Caspases since its involved in a plethora of physiological processes and in severe and chronic neurodegenerative processes. In this context, recent studies have indicated that CASP-2 is a potential therapeutic target for Alzheimer’s disease. It is therefore necessary to develop specific inhibitors which would constitute pharmacological tools to better understand the role of this protease in the physiology and pathology of the neuron. The current Caspases inhibitors are mostly tetra or pentapeptide sequences that reproduce the patterns preferentially recognized by these enzymes. During this thesis project, we used three identification strategies ; (i) a rational design approach of peptides targeting the active site, (ii) in silico design of peptides of the dimerization interface, (iii) rational an random screening of small organic molecules. Among these strategies, inhibition of the active site has been shown to be the most productive one. We have been able to demonstrate that the variation of the Alanine residue in P2 on the pattern VDVAD increased efficiency and selectivity parameters. Based on this observation, a serie of peptides “LJ” with various inhibitory mechanisms has been developed. Two compounds LJ2 and LJ3, demonstrated excellent inactivation and selectivity parameters toward CASP-2. In neuronal networks reconstructed in vitro, LJ2 and LJ3 protect against synapse loss. This thesis project opens the field to new perspectives on the functional level as well as on the therapeutic plan.
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Elodie David-Bosc. Rôle de la Caspase-2 au cours des processus neurodégénératifs associés au vieillissement. Conception rationnelle d’inhibiteurs sélectifs et évaluation sur des modèles biologique. Biochimie [q-bio.BM]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS173⟩. ⟨tel-02457149⟩

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