RESUMO
Stabilization of Cu(I) is ubiquitous within native copper proteins. Understanding how to stabilize Cu(I) within synthetic biomimetic systems is therefore desired towards biological applications. Peptoids are an important class of peptodomimetics, that can bind metal ions and stabilize them in their high oxidation state. Thus, to date, they were not used for Cu(I) binding. Here we show how the helical peptoid hexamer, having two 2,2'-bipyridine (Bipy) groups that face the same side of the helix, forms the intramolecular air stable Cu(I) complex. Further study of the binding site by rigorous spectroscopic techniques suggests that Cu(I) is tetracoordinated, binding to only three N atoms from the Bipy ligands and to the N-terminus of the peptoid's backbone. A set of control peptoids and experiments indicates that the Cu(I) stability and selectivity are dictated by the intramolecular binding, forced by the helicity of the peptoid, which can be defined as the second coordination sphere of the metal center.
RESUMO
Cu bound to amyloid-ß (Aß) 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-Aß. 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-Aß 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-Aß 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.
