196394-27-1Relevant academic research and scientific papers
Design of β-amyloid aggregation inhibitors from a predicted structural motif
Novick, Paul A.,Lopes, Dahabada H.,Branson, Kim M.,Esteras-Chopo, Alexandra,Graef, Isabella A.,Bitan, Gal,Pande, Vijay S.
, p. 3002 - 3010 (2012)
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 [Nle 35, 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-Pro 37]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.
