Mechanistic approaches for chemically modifying the coordination sphere of copper-amyloid-? complexes.

ABSTRACT: Neurotoxic implications of the interactions between Cu(I/II) and amyloid-? (A?) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to A? utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-A? was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-A? was able to disrupt binding of Cu(II) to A? and result in chemically modified A? with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-A? could stem from the molecule's ability to 1) interact with Cu(II)-A? and 2) foster copper-O₂ chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-A? at a metal-binding amino acid residue and consequently alter A?'s coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

SUBMITTER: Han J 

PROVIDER: S-EPMC7071886 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature