Stoichiometric inhibition of amyloid β-protein aggregation with peptides containing alternating α,α-disubstituted amino acids

We have prepared two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid β-protein (Aβ) that contain α,α-disubstituted amino acids at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus). We have studied the effects of AMY-1 and AMY-2 on the aggregation of Aβ and find that, at stoichiometric concentrations, both peptides completely stop Aβ fibril growth. Equimolar mixtures of AMY-1 and Aβ form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillar or fibrillar material even after prolonged periods of time (4.5 months). Also, 10 mol % of AMY-1 prevents Aβ self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillar or fibrillar aggregates. Circular dichroism spectroscopy of equimolar mixtures of AMY-1 and Aβ show that the secondary structure of the mixture changes over time and progresses to a predominantly β-sheet structure, which is consistent with the design of these inhibitors preferring a sheet-like conformation. Changing the position of the charged tail on the peptide, AMY-2 interacts with Aβ differently in that equimolar mixtures form large (∼1 μm) globular aggregates which do not progress to fibrils, but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the inhibitors act as cosurfactants that interfere with the native ability of Aβ to self-assemble by disrupting hydrophobic interactions either at the C-terminus or N-terminus of Aβ. Copyright © 2006 American Chemical Society.