Conformational restriction via cyclization in beta-amyloid peptide Abeta(1-28) leads to an inhibitor of Abeta(1-28) amyloidogenesis and cytotoxicity

Chem Biol. 2003 Feb;10(2):149-59. doi: 10.1016/s1074-5521(03)00022-x.

Abstract

The aggregation process of beta-amyloid peptide Abeta into amyloid is strongly associated with the pathology of Alzheimer's disease (AD). Aggregation may involve a transition of an alpha helix in Abeta(1-28) into beta sheets and interactions between residues 18-20 of the "Abeta amyloid core." We applied an i, i+4 cyclic conformational constraint to the Abeta amyloid core and devised side chain-to-side chain lactam-bridged cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28). In contrast to Abeta(1-28) and [Lys(17), Asp(21)]Abeta(1-28), cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) was not able to form beta sheets and cytotoxic amyloid aggregates. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) was able to interact with Abeta(1-28) and to inhibit amyloid formation and cytotoxicity. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) also interacted with Abeta(1-40) and interfered with its amyloidogenesis. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) or similarly constrained Abeta sequences may find therapeutic and diagnostic applications in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / toxicity
  • Benzothiazoles
  • Cell Survival / drug effects
  • Chromatography, Gel
  • Circular Dichroism
  • Congo Red
  • Cyclization
  • Drug Design
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Microscopy, Electron
  • Molecular Sequence Data
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / chemistry*
  • Peptide Fragments / toxicity
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Spectroscopy, Fourier Transform Infrared
  • Structure-Activity Relationship
  • Tetrazolium Salts
  • Thiazoles / metabolism
  • Tumor Cells, Cultured

Substances

  • Amyloid beta-Peptides
  • Benzothiazoles
  • Peptide Fragments
  • Tetrazolium Salts
  • Thiazoles
  • amyloid beta-protein (1-28)
  • thioflavin T
  • Congo Red
  • thiazolyl blue