Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease

Blood Cells Mol Dis. 2009 Mar-Apr;42(2):159-66. doi: 10.1016/j.bcmd.2008.11.002. Epub 2009 Jan 22.

Abstract

Gaucher disease is an autosomal recessive disorder. It is characterized by the accumulation of glucosylceramide in lysosomes of mononuclear phagocyte system, attributable to acid beta-glucosidase deficiency. The main consequences of this disease are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. At sub-inhibitory concentrations, several competitive inhibitors act as chemical chaperones by inducing protein stabilization and increasing enzymatic activity. Here we tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols with distinct degrees of lipophilicity as pharmacological chaperones for glucocerebrosidase (GBA). We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and aminocyclitol 1 in stably transfected cell lines, and an increment with NN-DNJ and aminocyclitol 4 in patient fibroblasts. These results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However, the development and analysis of new compounds is required in order to find more effective therapeutic agents that are active on a broader range of mutations.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Animals
  • COS Cells / drug effects
  • COS Cells / enzymology
  • Chlorocebus aethiops
  • Cyclitols / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Gaucher Disease / enzymology*
  • Gaucher Disease / genetics
  • Gaucher Disease / pathology
  • Genotype
  • Glucosylceramidase / antagonists & inhibitors
  • Glucosylceramidase / chemistry
  • Glucosylceramidase / genetics*
  • Glucosylceramidase / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Imino Sugars / pharmacology
  • Protein Folding / drug effects*
  • Protein Stability / drug effects
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism

Substances

  • Cyclitols
  • Enzyme Inhibitors
  • Imino Sugars
  • N-nonyl-1-deoxynojirimycin
  • Recombinant Fusion Proteins
  • 1-Deoxynojirimycin
  • miglustat
  • Glucosylceramidase