Foldamer-Mediated Structural Rearrangement Attenuates Aβ Oligomerization and Cytotoxicity

Sunil Kumar, Anja Henning-Knechtel, Ibrahim Chehade, Mazin Magzoub, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

The conversion of the native random coil amyloid beta (Aβ) into amyloid fibers is thought to be a key event in the progression of Alzheimer's disease (AD). A significant body of evidence suggests that the highly dynamic Aβ oligomers are the main causal agent associated with the onset of AD. Among many potential therapeutic approaches, one is the modulation of Aβ conformation into off-pathway structures to avoid the formation of the putative neurotoxic Aβ oligomers. A library of oligoquinolines was screened to identify antagonists of Aβ oligomerization, amyloid formation, and cytotoxicity. A dianionic tetraquinoline, denoted as 5, was one of the most potent antagonists of Aβ fibrillation. Biophysical assays including amyloid kinetics, dot blot, ELISA, and TEM show that 5 effectively inhibits both Aβ oligomerization and fibrillation. The antagonist activity of 5 toward Aβ aggregation diminishes with sequence and positional changes in the surface functionalities. 5 binds to the central discordant α-helical region and induces a unique α-helical conformation in Aβ. Interestingly, 5 adjusts its conformation to optimize the antagonist activity against Aβ. 5 effectively rescues neuroblastoma cells from Aβ-mediated cytotoxicity and antagonizes fibrillation and cytotoxicity pathways of secondary nucleation induced by seeding. 5 is also equally effective in inhibiting preformed oligomer-mediated processes. Collectively, 5 induces strong secondary structure in Aβ and inhibits its functions including oligomerization, fibrillation, and cytotoxicity.

Original languageEnglish (US)
Pages (from-to)17098-17108
Number of pages11
JournalJournal of the American Chemical Society
Volume139
Issue number47
DOIs
StatePublished - Nov 29 2017

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Oligomerization
Cytotoxicity
Amyloid
Oligomers
Conformations
Alzheimer Disease
Cloud seeding
Neuroblastoma
Libraries
Assays
Nucleation
Agglomeration
Enzyme-Linked Immunosorbent Assay
Modulation
Transmission electron microscopy
Kinetics
Fibers
Therapeutics

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Foldamer-Mediated Structural Rearrangement Attenuates Aβ Oligomerization and Cytotoxicity. / Kumar, Sunil; Henning-Knechtel, Anja; Chehade, Ibrahim; Magzoub, Mazin; Hamilton, Andrew.

In: Journal of the American Chemical Society, Vol. 139, No. 47, 29.11.2017, p. 17098-17108.

Research output: Contribution to journalArticle

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