I. , Considérations générales sur les propriétés enzymologiques de la Caspase-2

, Peptides aldéhydes -Inhibiteurs réversibles de première génération

.. .. Pouvoir-inhibiteur,

B. , Inhibiteurs irréversibles de seconde et troisième génération

, Présentation des molécules et hiérarchisation de l'effet

, Étude de l'effet des inhibiteurs sur un modèle d'apoptose dépendant de la Caspase-2 ... 216 4.1. Présentation du modèle HeLa -Vincristine

, Cytotoxicité des composés sur des neurones corticaux primaires

C. , Effets croisés des inhibiteurs des premières générations sur les Cathepsines

, Quantification des paramètres cinétiques de l'inhibition et efficacité des composés, p.223

D. Efficacité and .. .. ,

E. , Cytotoxicité sur des cultures primaires de neurones du Cortex

. Iv and . .. En,

C. , Hiérarchisation de l'effet et mécanisme d'action

, Type d'inhibition et quantification des paramètres cinétiques

E. Effet,

F. , Évaluation de la toxicité de h33 sur culture primaire de neurones corticaux

V. .. , 234 1. Structure et quantification des premiers effets sur les Caspases-2 et -3

.. .. Évaluation,

, 239 2. Hiérarchisation de l'effet grâce aux données IC50

, Efficacités inhibitrices des composés LJ2a, LJ2b, LJ3a et LJ3b

, Sélectivité vis-à-vis des protéases concurrentes

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, considérablement le pouvoir des inhibiteur sur les CASP-2 et -3 in vitro, avec des rapports kinact/KI de 1,2 .10 6 et 1,6.10 6 M -1 .s -1 respectivement

, Les résultats que nous avons obtenus sont différents de ceux obtenus par Chauvier

, M -1 .s -1 publié sur la CASP-3. Enfin, nous avons montré que le composé Q-D

, TRP-901, sur la CASP-3, nous pouvons supposer que si le peptide TRP-901 était déméthylé, l'effet du composé Q-DEVD-OPh serait nettement supérieur à celui du, pp.2-601

, Enfin, nous avons évalué la sélectivité du composé D2Me-TRP601 sur les Cathepsines

, M -1 .s -1 . L'effet étant nettement moins efficace que sur les CASP-2 et -3

C. Cependant, en 2011 avaient démontré le composé n'altérait pas de manière significative l'activité de 56 enzymes testées à 10 µM, parmi lesquelles : des kinases, des phosphatases, des protéases à sérine, cystéine et aspartate, des enzymes du métabolisme etc,? . De plus

, En effet, le composé Q-VD-OPh a un effet inactivateur modéré sur l'activité CASP-2 dans les tests enzymatiques in vitro, d'une part

, Dans d'autres modèles cellulaires il est connu que la vincristine induit une apoptose CASP

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, Dans ce contexte, des études récentes ont contribué à la validation de la CASP-2 en tant que cible thérapeutique potentielle de la maladie d'Alzheimer. Par conséquent, le développement d'inhibiteurs spécifiques constituerait des outils pharmacologiques qui permettraient de mieux appréhender les rôles de cette protéase dans la physiologie et pathologie du neurone. Les inhibiteurs de Caspases actuels sont majoritairement des séquences tétra ou pentapeptidiques qui reproduisent les motifs préférentiellement reconnus par les différents membres. Par exemple, la CASP-2 reconnait un motif pentapeptidique VDVAD qui est aussi reconnu par les CASP-3 et -7. Dans le cadre de ce travail de thèse, trois stratégies d'identification d'inhibiteurs ont été suivies ; (i) une approche de conception rationnelle de peptides inhibiteurs ciblant le site actif, (ii) conception in silico de peptides inhibiteurs de l'interface de dimérisation, (iii) criblage aléatoire et rationnel de petites molécules organiques. Parmi ces stratégies, l'inhibition du site actif s'est révélée être la plus fructueuse. Nous avons ainsi pu démontrer que des variations du résidu Alanine en P2 sur le motif initial VDVAD permettaient d'améliorer les paramètres de sélectivité et d'efficacité. Sur ce constat une série de peptides « LJ » avec des mécanismes d'inhibition variés a été développée. Parmi eux, deux composés LJ2 et LJ3 ont démontré un excellent potentiel inactivateur de la CASP-2, tout en conservant un effet préférentiel sur cette dernière. Nous avons également montré que ces deux composés protègent de la perte synaptique induite par des oligomères Ab1-42 dans des réseaux de neurones reconstruits in vitro, Les Caspases sont des endoprotéases à cystéine connues pour leurs rôles clé dans la régulation de l'apoptose et de l'inflammation. Parmi elles, la Caspase-2 (NEDD-2, ICH-1, CASP-2) est singulière de par ses multiples rôles dans le maintien de la stabilité génomique, la régulation du stress oxydant, la suppression de tumeur et également dans les processus neurodégénératifs aigus et chroniques. D'ailleurs, son rôle en tant qu'initiateur de la mort cellulaire a été démontré dans de nombreux modèles de stress neuronaux

. Mots-clés, Caspase-2 ; peptides inhibiteurs ; conception rationnelle ; inactivateurs sélectifs ; maladie d'Alzheimer