title: Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease.
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.
authors.affiliation: Departament de Genètica, Universitat de Barcelona, IBUB, CIBER de Enfermedades Raras (CIBERER), Av. Diagonal 645, Barcelona, Spain.
authors.forename: Gessamí
authors.initials: G
authors.lastname: Sánchez-Ollé
authors.forename: Joana
authors.initials: J
authors.lastname: Duque
authors.forename: Meritxell
authors.initials: M
authors.lastname: Egido-Gabás
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Montserrat
authors.initials: M
authors.lastname: Lluch
authors.forename: Amparo
authors.initials: A
authors.lastname: Chabás
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells / Q000187:drug effects / Q000201:enzymology; D002522:Chlorocebus aethiops; D054812:Cyclitols / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005838:Genotype; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D050111:Imino Sugars / Q000494:pharmacology; D017510:Protein Folding / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D054812:Cyclitols; D004791:Enzyme Inhibitors; D050111:Imino Sugars; C112150:N-nonyl-1-deoxynojirimycin; D011993:Recombinant Fusion Proteins; D017485:1-Deoxynojirimycin; C059896:miglustat; D005962:Glucosylceramidase