Design of ?-amyloid aggregation inhibitors from a predicted structural motif.

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

SUBMITTER: Novick PA 

PROVIDER: S-EPMC3766731 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature