Pour L'obtention Du Grade De Docteur Ès Sciences

The rapid growing number of patients diagnosed with a neurodegenerative disease and more particularly with Alzheimer’s disease (AD) has stimulated intensive research in determining and understanding biological phenomena causing such devastating diseases and hence allowing for the elaboration of adapted therapeutic treatments. These diseases are also commonly called “conformational” diseases because they result from the misfolding of a protein leading to the formation of self-associated β-sheets, which in turn give rise to the formation of oligomers, protofibrils as well as insoluble fibrils characterizing the plaques found in the brain of affected patients. Consequently, the investigation of such proteins, in particular of Amyloid β (Aβ) in the case of AD, is a limited and difficult task to achieve, which often leads to contradictory results. To overcome these difficulties and to be able to study the key steps of conformational transitions and misfolding of such peptides and proteins, our research group has developed a new tool, called switch-peptides, enabling to block (Soff state) and trigger (Son state) peptide folding at will (Figure). The introduction of a switch element S built from Ser, Thr or Cys residues disrupts the regular polypeptide chain by the insertion of an ester and a flexible C-C bond resulting in a conformational disconnection of P1 and P2 (Figure), i.e. in an unordered (random coil), nonfolded conformation. Each S element is protected by a protecting group Y (Soff state) that can be cleaved independently by adding a base, an enzyme or by light, depending on the chemical nature of Y. The cleavage of the different protecting groups Y triggers a spontaneous O to N