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Updated: Jun 23, 2026

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
Inhibition of gamma-secretase activity by helical beta-peptide foldamers
Yuki Imamura1, Naoto Watanabe, Naoki Umezawa
1Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603.
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by extensive extracellular deposition of amyloid-beta (Abeta) peptides as senile plaques, and inhibition of "amyloidogenic" amyloid precursor protein (APP) processing by gamma-secretase is an important strategy for prevention and treatment of AD. Here we show that beta-peptide foldamers designed to adopt a 12-helical conformation in solution are potent and specific inhibitors of gamma-secretase. Subtle modifications that disrupt helicity substantially reduce inhibitory potency, suggesting that helical conformation is critical for effective inhibition. These beta-peptides competed with helical peptide-type inhibitor, suggesting that they interact with the substrate binding site of gamma-secretase. The beta-peptide with inhibitory activity at nanomolar concentration should be a useful lead compound for development of gamma-secretase-specific inhibitors and molecular tools to explore substrate recognition by intramembrane proteases.
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