Pseudopeptide Designed to Inhibit Oligomerization and Redox Chemistry in Alzheimer?s Disease

J Phys Chem B. 2019 Jun 27;123(25):5206-5215. doi: 10.1021/acs.jpcb.9b01665. Epub 2019 Jun 12.

Abstract

Aggregation of amyloid beta peptide (A?) and inflammatory processes associated with the generation of superoxide, hydrogen peroxide, and hydroxyl radicals are responsible for neurotoxicity in Alzheimer?s disease. The latter are a result of the redox activity of copper-bound A? complexes with molecular oxygen. A ligand (PI1), previously designed to compete with A? for copper, and a pseudopeptide (SGC1) with a property of breaking the self-aggregation of A?, are attached to each other to form a new pseudopeptide (TGC1) in this study. Using a combination of density functional theory and molecular dynamics simulations, we show that TGC1 should have the ability to inhibit self-aggregation of A?, prevent the binding of copper to A?, and quench the redox activity of the copper. This trifunctional ligand is a good candidate for development into an anti-Alzheimer drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Copper / chemistry
  • Dimerization
  • Humans
  • Hydrogen Peroxide / chemistry
  • Molecular Dynamics Simulation
  • Oxidation-Reduction
  • Oxygen / chemistry
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Aggregates / drug effects
  • Superoxides / chemistry
  • Thermodynamics

Substances

  • Amyloid beta-Peptides
  • Peptides
  • Protein Aggregates
  • Superoxides
  • Copper
  • Hydrogen Peroxide
  • Oxygen