Iminosugar-Dihydroazulenes as Mutant L444P Glucocerebrosidase Enhancers

Chem Biodivers. 2024 Aug;21(8):e202401104. doi: 10.1002/cbdv.202401104. Epub 2024 Jul 23.

Abstract

A remarkable enhancer of human glucocerebrosidase enzyme (GCase) was identified among a set of dihydroazulene-tagged iminosugars. An unprecedented 3.9-fold increase in GCase activity was detected on fibroblasts bearing the homozygous L444P mutation, which is frequently associated with neuronopathic Gaucher forms, and which commonly results refractory to chaperone-induced refolding.

Keywords: Click chemistry; Enzyme modulators; Gaucher disease; Neuronopathic disorder; Photochromism.

MeSH terms

  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gaucher Disease / drug therapy
  • Gaucher Disease / genetics
  • Gaucher Disease / metabolism
  • Glucosylceramidase* / antagonists & inhibitors
  • Glucosylceramidase* / genetics
  • Glucosylceramidase* / metabolism
  • Humans
  • Imino Sugars / chemical synthesis
  • Imino Sugars / chemistry
  • Imino Sugars / metabolism
  • Imino Sugars / pharmacology
  • Molecular Structure
  • Mutation*

Substances

  • Glucosylceramidase
  • Imino Sugars