'Click' assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4523-4528. doi: 10.1016/j.bmcl.2014.07.077. Epub 2014 Aug 9.

Abstract

Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer's disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide-alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death.

Keywords: Alzheimer’s disease; Amyloid beta-peptides; Click chemistry; Glycoclusters; Osmolytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Click Chemistry*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glycoconjugates / chemical synthesis
  • Glycoconjugates / chemistry
  • Glycoconjugates / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Structure-Activity Relationship
  • Trehalose / analogs & derivatives*
  • Trehalose / chemistry

Substances

  • Amyloid beta-Peptides
  • Glycoconjugates
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • Trehalose