Design of β-amyloid aggregation inhibitors from a predicted structural motif

J Med Chem. 2012 Apr 12;55(7):3002-10. doi: 10.1021/jm201332p. Epub 2012 Mar 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Solutions