Systematic Development of Small Molecules to Inhibit Specific Microscopic Steps of Aβ42 Aggregation in Alzheimer's Disease

Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E200-E208. doi: 10.1073/pnas.1615613114. Epub 2016 Dec 23.

Abstract

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.

Keywords: Alzheimer’s disease; amyloid-β peptide; drug discovery; protein aggregation; protein misfolding.

MeSH terms

  • Alzheimer Disease
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Caenorhabditis elegans
  • Cerebrospinal Fluid / chemistry
  • Drug Discovery*
  • Humans
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Small Molecule Libraries

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Small Molecule Libraries
  • amyloid beta-protein (1-42)