Effect of Helical Conformation and Side Chain Structure on γ-Secretase Inhibition by β-Peptide Foldamers: Insight into Substrate Recognition

Substrate-selective inhibition or modulation of the activity of gamma-secretase, which is responsible for the generation of amyloid-beta peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical beta-peptide foldamers are potent and specific inhibitors of gamma-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 gamma-secretase-inhibitory activity. The substrate selectivity of the inhibitory activity was also quite sensitive to the class of side chain group incorporated.