Study of the capacity of 3 classes of ligands to eliminate Cu(I) and Cu(II) from the beta-amyloid peptide involved in Alzheimer's disease in

A therapeutic approach that has been explored in the context of Alzheimer's disease (AD) involves the removal of the redox-active copper ions (Cu) that are bound into the amyloidogenic peptide implicated in AD (amyloid-β peptide, Aβ), in the synaptic cleft. In this regard, our current research focuses on the development of ligands, targeting Cu(II) or Cu(I), or both redox states, able to inhibit the redox cycling of Cu and the production of the toxic reactive oxygen species (ROS) it generates. The ligands under consideration here include macrocycle N-based thioether (A), thiosemicarbazone derivatives (B), and modified ATCUN peptides (C). Our project aims to gain insights into the binding of Cu(I), Cu(II) and Zn(II) with the ligands and to monitor the Cu removal from the Cu(Aβ) in biological conditions with and without Zn(II). The present study also intends to evaluate the ability of the ligand to redistribute the Cu(I) to glutathione (GSH), an abundant intracellular component.