Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Jiyeon Han, Hyuck Jin Lee, Kyu Yeon Kim, Geewoo Nam, Junghyun Chae, Mi Hee Lim

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5160-5167
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number10
DOIs
StatePublished - 10 Mar 2020

Keywords

  • Amyloid-β
  • Copper
  • Copper–O chemistry
  • Residue-specific modifications
  • Small molecule

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