Inhibition of γ-secretase activity by helical β-peptide foldamers

Yuki Imamura, Naoto Watanabe, Naoki Umezawa, Takeshi Iwatsubo, Nobuki Kato, Taisuke Tomita, Tsunehiko Higuchi

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by extensive extracellular deposition of amyloid-β (Aβ) peptides as senile plaques, and inhibition of "amyloidogenic" amyloid precursor protein (APP) processing by γ-secretase is an important strategy for prevention and treatment of AD. Here we show that β-peptide foldamers designed to adopt a 12-helical conformation in solution are potent and specific inhibitors of γ-secretase. Subtle modifications that disrupt helicity substantially reduce inhibitory potency, suggesting that helical conformation is critical for effective inhibition. These β-peptides competed with helical peptide-type inhibitor, suggesting that they interact with the substrate binding site of γ-secretase. The β-peptide with inhibitory activity at nanomolar concentration should be a useful lead compound for development of γ-secretase-specific inhibitors and molecular tools to explore substrate recognition by intramembrane proteases.

Original languageEnglish
Pages (from-to)7353-7359
Number of pages7
JournalJournal of the American Chemical Society
Volume131
Issue number21
DOIs
Publication statusPublished - 2009 Jun 3
Externally publishedYes

ASJC Scopus subject areas

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

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    Imamura, Y., Watanabe, N., Umezawa, N., Iwatsubo, T., Kato, N., Tomita, T., & Higuchi, T. (2009). Inhibition of γ-secretase activity by helical β-peptide foldamers. Journal of the American Chemical Society, 131(21), 7353-7359. https://doi.org/10.1021/ja9001458