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-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer's disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn²⁺ 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 Cu²⁺ from Cu-Aβ 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-Aβ 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.

Keywords: Alzheimer's disease; Cu chelators; Zn; amyloids; peptides; peptoids.