Abstract
Drug design studies targeting one of the primary toxic agents in Alzheimer's disease, soluble oligomers of amyloid β-protein (Aβ), have been complicated by the rapid, heterogeneous aggregation of Aβ and the resulting difficulty to structurally characterize the peptide. To address this, we have developed [Nle(35), D-Pro(37)]Aβ(42), a substituted peptide inspired from molecular dynamics simulations which forms structures stable enough to be analyzed by NMR. We report herein that [Nle(35), D-Pro(37)]Aβ(42) stabilizes the trimer and prevents mature fibril and β-sheet formation. Further, [Nle(35), D-Pro(37)]Aβ(42) interacts with WT Aβ(42) and reduces aggregation levels and fibril formation in mixtures. Using ligand-based drug design based on [Nle(35), D-Pro(37)]Aβ(42), a lead compound was identified with effects on inhibition similar to the peptide. The ability of [Nle(35), D-Pro(37)]Aβ(42) and the compound to inhibit the aggregation of Aβ(42) provides a novel tool to study the structure of Aβ oligomers. More broadly, our data demonstrate how molecular dynamics simulation can guide experiment for further research into AD.