A Copper-Binding\nPeptide with Therapeutic Potential\nagainst Alzheimer′s Disease: From the Blood–Brain Barrier\nto Metal Competition

Alzheimer’s disease (AD) is the most common form\nof dementia\nworldwide. AD brains are characterized by the accumulation of amyloid-β\npeptides (Aβ) that bind Cu<sup>2+</sup> and have been associated\nwith several neurotoxic mechanisms. Although the use of copper chelators\nto prevent the formation of Cu<sup>2+</sup>-Aβ complexes has\nbeen proposed as a therapeutic strategy, recent studies show that\ncopper is an important neuromodulator that is essential for a neuroprotective\nmechanism mediated by Cu<sup>2+</sup> binding to the cellular prion\nprotein (PrP<sup>C</sup>). Therefore, in addition to metal selectivity\nand blood–brain barrier (BBB) permeability, an emerging challenge\nfor copper chelators is to prevent the formation of neurotoxic Cu<sup>2+</sup>-Aβ species without perturbing the neuroprotective\nCu<sup>2+</sup>-PrP<sup>C</sup> interaction. Previously, we reported\nthe design of a tetrapeptide (TP) that withdraws Cu<sup>2+</sup> from\nAβ(1–16) and impacts the Cu<sup>2+</sup>-induced aggregation\nof Aβ(1–40). In this study, we improved the drug-like\nproperties of TP in a BBB model, evaluated the metal selectivity of\nthe optimized peptide (TP*), and tested its effect on Cu<sup>2+</sup> coordination to PrP<sup>C</sup> and proteins involved in copper\ntrafficking, such as copper transporter 1 and albumin. Our results\nshow that changing the stereochemistry of the first residue prevents\nTP degradation in the BBB model and coadministration of TP with a\npeptide that increases BBB permeability allows its passage through\nthe BBB model. TP* is highly selective toward Cu<sup>2+</sup> in the\npresence of Zn<sup>2+</sup> ions, transfers Cu<sup>2+</sup> to copper-trafficking\nproteins, and forms a ternary TP*-Cu<sup>2+</sup>-PrP species that\ndoes not perturb the physiological conformation of PrP and displays\nonly a minor impact in the neuroprotective Cu<sup>2+</sup>-dependent\ninteraction of PrP<sup>C</sup> with the <i>N</i>-methyl-d-aspartate receptor. Overall, these results show that TP* displays\ndesirable features for a copper chelator with therapeutic potential\nagainst AD. Moreover, this is the first study that explores the effect\nof a Cu<sup>2+</sup> chelator with therapeutic potential for AD on\nCu<sup>2+</sup> coordination to PrP<sup>C</sup> (an emerging key player\nin AD pathology), integrating recent knowledge about metalloproteins\ninvolved in AD with the design of copper chelators against AD.