Document Detail

A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.
MedLine Citation:
PMID:  23337983     Owner:  NLM     Status:  MEDLINE    
Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of β-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp(2)-iminosugar type, namely 5N,6S-(N'-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant β-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human β-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N'-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 β-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of β-Gal mutants.
Tomoko Takai; Katsumi Higaki; Matilde Aguilar-Moncayo; Teresa Mena-Barragán; Yuki Hirano; Kei Yura; Liang Yu; Haruaki Ninomiya; M Isabel García-Moreno; Yasubumi Sakakibara; Kousaku Ohno; Eiji Nanba; Carmen Ortiz Mellet; José M García Fernández; Yoshiyuki Suzuki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-22
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-10-22     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  526-32     Citation Subset:  IM    
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MeSH Terms
1-Deoxynojirimycin / analogs & derivatives*,  pharmacology
Administration, Oral
Bicyclo Compounds, Heterocyclic / pharmacology
Cells, Cultured
Computational Biology
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Fibroblasts / drug effects,  metabolism
Gangliosidosis, GM1 / drug therapy*,  genetics
Imino Sugars / chemistry,  pharmacology
Lysosomes / metabolism
Mice, Inbred C57BL
Mice, Knockout
Molecular Chaperones / pharmacology*
Mucopolysaccharidosis IV / drug therapy,  genetics
Recombination, Genetic
beta-Galactosidase / chemistry,  genetics
Reg. No./Substance:
0/1-deoxygalactonojirimycin; 0/5N,6S-(N'-butyliminomethylidene)-6-thio-1-deoxygalactonojirimycin; 0/Bicyclo Compounds, Heterocyclic; 0/Enzyme Inhibitors; 0/Imino Sugars; 0/Molecular Chaperones; 19130-96-2/1-Deoxynojirimycin; EC

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