title: A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.
abstract: 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.
authors: Tottori University, Yonago, Japan.
authors: Tomoko
authors: T
authors: Takai
authors: Katsumi
authors: K
authors: Higaki
authors: Matilde
authors: M
authors: Aguilar-Moncayo
authors: Teresa
authors: T
authors: Mena-Barragán
authors: Yuki
authors: Y
authors: Hirano
authors: Kei
authors: K
authors: Yura
authors: Liang
authors: L
authors: Yu
authors: Haruaki
authors: H
authors: Ninomiya
authors: M Isabel
authors: MI
authors: García-Moreno
authors: Yasubumi
authors: Y
authors: Sakakibara
authors: Kousaku
authors: K
authors: Ohno
authors: Eiji
authors: E
authors: Nanba
authors: Carmen
authors: C
authors: Ortiz Mellet
authors: José M
authors: JM
authors: García Fernández
authors: Yoshiyuki
authors: Y
authors: Suzuki
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D019295:Computational Biology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000235:genetics; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000494:pharmacology*; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy / Q000235:genetics; D009154:Mutation; D011995:Recombination, Genetic; D001616:beta-Galactosidase / Q000737:chemistry / Q000235:genetics
chemical_list: C583852:5N,6S-(N'-butyliminomethylidene)-6-thio-1-deoxygalactonojirimycin; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D018832:Molecular Chaperones; D017485:1-Deoxynojirimycin; C090092:migalastat; D001616:beta-Galactosidase