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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Enheter & grupper
Externa organisationer
  • University of Cambridge
  • Skåne University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper
  • Neurologi

Nyckelord

Originalspråkengelska
Sidor (från-till)E200-E208
TidskriftProceedings of the National Academy of Sciences of the United States of America
Volym114
Utgivningsnummer2
StatusPublished - 2017 jan 10
PublikationskategoriForskning
Peer review utfördJa