Inhibition of gamma-secretase activity by helical beta-peptide foldamers.
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.
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603.
Yuki
Y
Imamura
Naoto
N
Watanabe
Naoki
N
Umezawa
Takeshi
T
Iwatsubo
Nobuki
N
Kato
Taisuke
T
Tomita
Tsunehiko
T
Higuchi
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012996:Solutions
D004791:Enzyme Inhibitors; D010455:Peptides; D012996:Solutions; D053829:Amyloid Precursor Protein Secretases