Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease.
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.
Sánchez-Ollé
Gessamí
G
Departament de Genètica, Universitat de Barcelona, IBUB, CIBER de Enfermedades Raras (CIBERER), Av. Diagonal 645, Barcelona, Spain.
Duque
Joana
J
Egido-Gabás
Meritxell
M
Casas
Josefina
J
Lluch
Montserrat
M
Chabás
Amparo
A
Grinberg
Daniel
D
Vilageliu
Lluïsa
L
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
D054812:Cyclitols; D004791:Enzyme Inhibitors; D050111:Imino Sugars; C112150:N-nonyl-1-deoxynojirimycin; D011993:Recombinant Fusion Proteins; D017485:1-Deoxynojirimycin; C059896:miglustat; D005962:Glucosylceramidase