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

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), β-1- C-butenyl-1-deoxygalactonojirimycin ( 8), 2,3-dideoxy-β-1- C-ethyl-1-deoxygalactonojirimycin ( 9), and 6- O-β- d-glucopyranosyl-2,3-dideoxy-β-1- C-ethyl-1-deoxygalactonojirimycin ( 10). β-1- C-Butyl-1-deoxygalactonojirimycin ( 7) and compound 8 were found to be better inhibitors of α-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome α-galactosidase A (α-Gal A) with a K i value of 0.5 μM. Furthermore, DIA improved the thermostability of α-Gal A in vitro and increased intracellular α-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3 days. 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.