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

Gaucher's disease (GD), mainly caused by a defect of acid beta-glucosidase (beta-Glu), is the most common form of sphingolipidosis. We have previously shown that the carbohydrate mimic and inhibitor of beta-Glu, N-octyl-beta-valienamine (NOV), could increase the protein level and enzyme activity of various mutant beta-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 beta-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 beta-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 beta-Glu. Copyright 2009 Elsevier Inc. All rights reserved.