title: Chaperone activity of bicyclic nojirimycin analogues for Gaucher mutations in comparison with N-(n-nonyl)deoxynojirimycin.
abstract: Gaucher disease (GD), the most prevalent lysosomal storage disorder, is caused by mutations of lysosomal beta-glucosidase (acid beta-Glu, beta-glucocerebrosidase); these mutations result in protein misfolding. Some inhibitors of this enzyme, such as the iminosugar glucomimetic N-(n-nonyl)-1-deoxynojirimycin (NN-DNJ), are known to bind to the active site and stabilize the proper folding for the catalytic form, acting as "chemical chaperones" that facilitate transport and maturation of acid beta-Glu. Recently, bicyclic nojirimycin (NJ) analogues with structure of sp2 iminosugars were found to behave as very selective, competitive inhibitors of the lysosomal beta-Glu. We have now evaluated the glycosidase inhibitory profile of a series of six compounds within this family, namely 5-N,6-O-(N'-octyliminomethylidene-NJ (NOI-NJ), the 6-thio and 6-amino-6-deoxy derivatives (6S-NOI-NJ and 6N-NOI-NJ) and the corresponding galactonojirimycin (GNJ) counterparts (NOI-GNJ, 6S-NOI-GNJ and 6N-NOI-GNJ), against commercial as well as lysosomal glycosidases. The chaperone effects of four selected candidates (NOI-NJ, 6S-NOI-NJ, 6N-NOI-NJ, and 6S-NOI-GNJ) were further evaluated in GD fibroblasts with various acid beta-Glu mutations. The compounds showed enzyme enhancement on human fibroblasts with N188S, G202R, F213I or N370S mutations. The chaperone effects of the sp2 iminosugar were generally stronger than those observed for NN-DNJ; this suggests that these compounds are promising candidates for clinical treatment of GD patients with a broad range of beta-Glu mutations, especially for neuronopathic forms of Gaucher disease.
authors.affiliation: Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho, Yonago 683-8504, Japan.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Luan
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Matilde
authors.initials: M
authors.lastname: Aguilar-Moncayo
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: M Isabel
authors.initials: MI
authors.lastname: García-Moreno
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D009154:Mutation; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D018832:Molecular Chaperones; C112150:N-nonyl-1-deoxynojirimycin; D017485:1-Deoxynojirimycin; D005962:Glucosylceramidase; C013626:nojirimycin