A Water‐Soluble Peptoid Chelator that Can Remove Cu²⁺ from Amyloid‐β Peptides and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease

Abstract

Cu bound to amyloid-b (Ab) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimers disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Ab. This chelator should compete with Zn 2+ ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex. Herein we describe P3, a water-soluble peptidomimetic chelator that selectively removes Cu 2+ from Cu-Ab in the presence of Zn and prevent the formation of ROS even in a reductive environment. We demonstrate, based on extensive spectroscopic analysis, that although P3 extracts Zn from Cu,Zn-Ab faster than it removes Cu, the formed Zn complexes are kinetic products that further dissociate, while CuP3 is formed as an exclusive stable thermodynamic product. Our unique findings, combined with the bioavailability of peptoids, make P3 an excellent drug candidate in the context of AD.

Ability of Azathiacyclen Ligands To Stop Cu(Aβ)‐Induced Production of Reactive Oxygen Species: [3N1S] Is the Right Donor Set

“…Such a study is currently in progress. Not only is the thermodynamic selectivity of Cu II over Zn II at play in this case (in contrast to previous reports [63–66] ), but also kinetics. The results obtained, their interpretation and the mechanisms at play are very complex and will be reported in a forthcoming publication.…”