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제125회 대한화학회 학술발표회 및 총회 Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

2020년 1월 28일 11시 23분 43초
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Inorganic Chemistry
저자 및
Jiyeon Han, Mi Hee Lim*
Department of Chemistry, Korea Advanced Institute of Science and Technology, Korea
Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) 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 Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)–Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)–Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)–Aβ could stem from the molecule’s ability to 1) interact with Cu(II)–Aβ and 2) foster copper–O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)–Aβ at a metal-binding amino acid residue and consequently alter Aβ’s coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.