Transfer of Copper from an Amyloid to a Natural Copper‐Carrier Peptide with a Specific Mediating Ligand. Issue 47 (30th September 2015)

• Record Type: Journal Article
• Authors: Nguyen, Michel; Bijani, Christian; Martins, Nathalie; Meunier, Bernard; Robert, Anne
• Is Part Of: Chemistry. Volume 21:Issue 47(2015)
• Page Start: 17085
• Page End: 17090
• Publication Date: 2015-09-30
• Subjects: alzheimer's disease -- aminoquinoline -- chelates -- copper -- medicinal chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201502824
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The oxidative stress that arises from the catalytic reduction of dioxygen by Cu II/I ‐loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis‐8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu II from Cu–Aβ1–16 and then completely release Cu I in the presence of glutathione to provide a Cu I –glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper–protein complexes. These data demonstrate that bis‐8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu–amyloid complexes to regular copper–protein complexes. These copper‐specific ligands assist GSH to recycle Cu I in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8‐hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu–β‐amyloid complexes. Abstract : Copper homeostasis : Copper is put back into physiological function using bis(8‐aminoquinoline) ligands, which are specific chelators of Cu II that are able to extract the metal ions from Cuamyloid complexes. These ligands show promise as drug candidates to assist glutathione in re‐establishing copper homeostasis in an Alzheimer′s disease brain and consequently preventing oxidative neuron damage (see scheme).