Ability of new N-based thioether and thiol(ate) ligands (L[N,Sn], n=2 or 3) to remove Cu(I) from the amyloid-beta peptide involved in Alzhei

One therapeutic approach explored in Alzheimer's disease consists to remove the redox active copper ions bound into the amyloidogenic peptide involved in the disease (amyloid-β peptide, Aβ). Despite several years of development, this strategy did not yield expected results in terms of therapeutic effects. While most of the ligands studied were thought to target the Cu(II), Cu(I) ligands have been overlooked and might be the missing piece of the puzzle for the strategy to be effective. In this context we have developed N-based thioether and thiolate ligands dedicated to the removal of Cu(I) from Aβ to fill this gap. The project aim to gain insights into the binding site of Cu(I) (and Zn(II)) with the designed ligands and to monitor the metal removal from the Cu(Aβ) species in presence and in absence of Zn(II). Zn(II) is also present in high amount in the synaptic cleft; its impacts on Cu detoxification by the designed ligands must thus be evaluated.