Design of β-Amyloid Aggregation Inhibitors from a Predicted Structural Motif

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 [Nle³⁵, d-Pro³⁷]­Aβ₄₂, a substituted peptide inspired from molecular dynamics simulations which forms structures stable enough to be analyzed by NMR. We report herein that [Nle³⁵, d-Pro³⁷]­Aβ₄₂ stabilizes the trimer and prevents mature fibril and β-sheet formation. Further, [Nle³⁵, d-Pro³⁷]­Aβ₄₂ interacts with WT Aβ₄₂ and reduces aggregation levels and fibril formation in mixtures. Using ligand-based drug design based on [Nle³⁵, d-Pro³⁷]­Aβ₄₂, a lead compound was identified with effects on inhibition similar to the peptide. The ability of [Nle³⁵, d-Pro³⁷]­Aβ₄₂ and the compound to inhibit the aggregation of Aβ₄₂ 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.