2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease

Bioorg Med Chem. 2010 Jun 1;18(11):3790-4. doi: 10.1016/j.bmc.2010.04.048. Epub 2010 Apr 21.


Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-d-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5muM. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme.

MeSH terms

  • Campanulaceae / chemistry
  • Fabry Disease / drug therapy*
  • Humans
  • Imino Sugars / isolation & purification
  • Molecular Chaperones / chemistry*
  • Mutant Proteins / metabolism
  • Phytotherapy / methods*
  • Piperidines / isolation & purification
  • Plant Extracts / chemistry
  • Protein Transport
  • Pyrrolidines / isolation & purification
  • Sugar Alcohols / isolation & purification
  • Sugar Alcohols / therapeutic use*
  • alpha-Galactosidase / antagonists & inhibitors


  • Imino Sugars
  • Molecular Chaperones
  • Mutant Proteins
  • Piperidines
  • Plant Extracts
  • Pyrrolidines
  • Sugar Alcohols
  • altritol
  • alpha-Galactosidase