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Chaperone Activity of Bicyclic Nojirimycin Analogues for Gaucher Mutations in Comparison with N-(n-nonyl)Deoxynojirimycin

AuthorsLuan, Zhuo; Higaki, Katsumi; Aguilar Moncayo, Matilde ; Ninomiya, Haruaki; Ohno, Kousaku; García Moreno, María Isabel; Ortiz-Mellet, Carmen; García-Fernández, José Manuel; Suzuki, Yoshiyuki
KeywordsGaucher disease
Imino sugars
Medicinal chemistry
Issue Date14-Oct-2009
CitationChemBioChem 10(17): 2780-2792 (2009)
AbstractGaucher disease (GD), the most prevalent lysosomal storage disorder, is caused by mutations of lysosomal β-glucosidase (acid β-Glu, β-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 β-Glu. Recently, bicyclic nojirimycin (NJ) analogues with structure of sp2 iminosugars were found to behave as very selective, competitive inhibitors of the lysosomal β-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 β-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 β-Glu mutations, especially for neuronopathic forms of Gaucher disease.
Description13 páginas, 2 figuras, 3 tablas, 4 esquemas
Publisher version (URL)http://dx.doi.org/10.1002/cbic.200900442
Appears in Collections:(IIQ) Artículos
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