The pharmacological chaperone effect of N-octyl-β-valienamine on human mutant acid β-glucosidases

Gaucher's disease (GD), mainly caused by a defect of acid β-glucosidase (β-Glu), is the most common form of sphingolipidosis. We have previously shown that the carbohydrate mimic and inhibitor of β-Glu, N-octyl-β-valienamine (NOV), could increase the protein level and enzyme activity of various mutant β-Glus in cultured GD fibroblasts and in COS cells, suggesting that NOV acts as a pharmacological chaperone to accelerate transport and maturation of these mutant enzymes. In present study, we continued to investigate the chaperone characteristics of NOV. More importantly, chaperone activities of NOV were evaluated in COS cells transiently expressing ten new, recombinant β-Glu mutants with mutations located in domain I, II and III. NOV was only effective on the T369M mutation, located in domain III. As we suggested in a previous study, domain III may be a prerequisite for pharmacological rescue of the mutant β-Glu by NOV. These characteristics of NOV could provide potential therapeutic chaperone properties that would be useful in the treatment of GD with neurological manifestations due to gene mutations in β-Glu.