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

• Published in: Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3002-3010
• Main Authors: Novick, Paul A, Lopes, Dahabada H, Branson, Kim M, Esteras-Chopo, Alexandra, Graef, Isabella A, Bitan, Gal, Pande, Vijay S
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Animals; Cell Survival - drug effects; Circular Dichroism; Models, Molecular; PC12 Cells; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - toxicity; Polymerization; Protein Structure, Secondary; Rats; Solutions; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201332p

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.