Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology

J Med Chem. 2012 Nov 8;55(21):8997-9008. doi: 10.1021/jm3008618. Epub 2012 Oct 5.

Abstract

An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Animals
  • Apolipoprotein E4 / chemistry
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism*
  • Brain Injuries / metabolism
  • Endoplasmic Reticulum / metabolism
  • Golgi Apparatus / metabolism
  • Humans
  • Lipid Metabolism
  • Models, Molecular
  • Molecular Targeted Therapy
  • Neurons / metabolism
  • Protein Conformation
  • Protein Folding / drug effects*
  • Protein Transport
  • Proteostasis Deficiencies / drug therapy*
  • Proteostasis Deficiencies / metabolism
  • Structure-Activity Relationship

Substances

  • Apolipoprotein E4