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Closed Access item A Fluorescent sp2-Iminosugar With Pharmacological Chaperone Activity for Gaucher Disease: Synthesis and Intracellular Distribution Studies

Authors:Luan, Zhuo
Higaki, Katsumi
Aguilar Moncayo, Matilde
Li, Linjing
Ninomiya, Haruaki
Nanba, Eiji
Ohno, Kousaku
García Moreno, María Isabel
Ortiz-Mellet, Carmen
García-Fernández, José Manuel
Suzuki, Yoshiyuki
Keywords:Chaperones, Fluorescent probes, Gaucher disease, Glucosidases, Iminosugars
Issue Date:9-Nov-2010
Publisher:Wiley-VCH
Citation:ChemBioChem 11(17): 2453-2464 (2010)
Abstract:Gaucher disease (GD) is the most prevalent lysosomal-storage disorder, it is caused by mutations of acid β-glucosidase (β-glucocerebrosidase; β-Glu). Recently, we found that bicyclic nojirimycin (NJ) derivatives of the sp2-iminosugar type, including the 6-thio-N′-octyl-(5N,6S)-octyliminomethylidene derivative (6S-NOI-NJ), behaved as very selective competitive inhibitors of the lysosomal β-Glu and exhibited remarkable chaperone activities for several GD mutations. To obtain information about the cellular uptake pathway and intracellular distribution of this family of chaperones, we have synthesized a fluorescent analogue that maintains the fused piperidine–thiazolidine bicyclic skeleton and incorporates a dansyl group in the N′-substituent, namely 6-thio-(5N,6S)-[4-(N′-dansylamino)butyliminomethylidene]nojirimycin (6S-NDI-NJ). This structural modification does not significantly modify the biological activity of the glycomimetic as a chemical chaperone. Our study showed that 6S-NDI-NJ is mainly located in lysosome-related organelles in both normal and GD fibroblasts, and the fluorescent intensity of 6S-NDI-NJ in the lysosome is related to the β-Glu concentration level. 6S-NDI-NJ also can enter cultured neuronal cells and act as a chaperone. Competitive inhibition studies of 6S-NDI-NJ uptake in fibroblasts showed that high concentrations of D-glucose have no effect on chaperone internalization, suggesting that it enters the cells through glucose-transporter-independent mechanisms.
Description:12 páginas
Publisher version (URL):http://dx.doi.org/10.1002/cbic.201000323
URI:http://hdl.handle.net/10261/36521
ISSN:1429-4227
E-ISSNmetadata.dc.identifier.doi = DOI:1439-7633
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Appears in Collections:(IIQ) Artículos

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