title: Design of β-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 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.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA. pnovick@stanford.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Novick
authors.forename: Dahabada H
authors.initials: DH
authors.lastname: Lopes
authors.forename: Kim M
authors.initials: KM
authors.lastname: Branson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Esteras-Chopo
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Graef
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D008958:Models, Molecular; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D058105:Polymerization; D017433:Protein Structure, Secondary; D051381:Rats; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions