Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer's disease

Research output: Contribution to journalArticle

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 readout 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.

Details

Authors
  • Johnny Habchi
  • Sean Chia
  • Ryan Limbocker
  • Benedetta Mannini
  • Minkoo Ahn
  • Michele Perni
  • Oskar Hansson
  • Paolo Arosio
  • Janet R Kumita
  • Pavan Kumar Challa
  • Samuel I A Cohen
  • Sara Linse
  • Christopher M Dobson
  • Tuomas P J Knowles
  • Michele Vendruscolo
Organisations
External organisations
  • University of Cambridge
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
  • Neurology

Keywords

  • Alzheimer's disease, Amyloid-β peptide, Drug discovery, Protein aggregation, Protein misfolding
Original languageEnglish
Pages (from-to)E200-E208
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number2
Publication statusPublished - 2017 Jan 10
Publication categoryResearch
Peer-reviewedYes