Effect of helical conformation and side chain structure on γ-secretase inhibition by β-peptide foldamers: Insight into substrate recognition

Yuki Imamura, Naoki Umezawa, Satoko Osawa, Naoaki Shimada, Takuya Higo, Satoshi Yokoshima, Tohru Fukuyama, Takeshi Iwatsubo, Nobuki Kato, Taisuke Tomita, Tsunehiko Higuchi

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Substrate-selective inhibition or modulation of the activity of γ-secretase, which is responsible for the generation of amyloid-β peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical β-peptide foldamers are potent and specific inhibitors of γ-secretase. Here we report identification of target site of the foldamers by using a photoaffinity probe. The photoprobe directly and specifically labeled the N-terminal fragment of presenilin 1, in which the initial substrate docking site is predicted to be located. We also optimized the foldamer structure by preparing a variety of derivatives and obtained two highly potent foldamers by incorporation of a hydrophilic and neutral functional group into the parent structure. The class of side chain functional group and the position of incorporation were both important for γ-secretase-inhibitory activity. The substrate selectivity of the inhibitory activity was also quite sensitive to the class of side chain group incorporated.

Original languageEnglish
Pages (from-to)1443-1454
Number of pages12
JournalJournal of Medicinal Chemistry
Volume56
Issue number4
DOIs
Publication statusPublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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