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

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.

Tools of the Trade: Investigations into Design Strategies of Small Molecules to Target Components in Alzheimer's Disease

“…13 Helical β‐peptide foldamers that mimic the transmembrane domain of C99, a substrate of γ‐secretase, might be useful for the generation of NOTCH‐sparing inhibitors for γ‐secretase 13. Imamura et al identified the ( S , S )‐2‐aminocyclopentanecarboxylic acid (ACPC) dodecamer as a potential foldamer framework, in addition to discerning its target site 14. Through derivation and optimization of the foldamer scaffolds, some substrate recognition properties of γ‐secretase were revealed; this might supply helpful information for further construction of selective γ‐secretase inhibitors 14…”

An overview of peptide and peptoid foldamers in medicinal chemistry

“…Consequently, the number of pharmacophore points should be relatively low. For a deeper understanding of the mode of action and binding of these oligomers, photoaffinity probes and side-chain fine-tuning have been performed [85]. The photoaffinity probes demonstrated that the oligomers selectively bind the N-terminal fragment of presenilin 1.…”

Exploiting Aromatic Interactions for β‐Peptide Foldamer Helix Stabilization: A Significant Design Element

“…They possess numerous interesting features, as they can bind to non‐drugable proteins to inhibit pharmacologically important protein–protein interactions. Accordingly, they are able to inhibit the interaction of p53‐hDM2 proteins,2 they can bind to HIV fusion protein,3 or to β‐amyloid peptide4 or inhibit its formation 5. Moreover, they are RNA‐binding oligomers that inhibit HIV proliferation 6…”