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dc.contributor.authorLuan, Zhuo-
dc.contributor.authorHigaki, Katsumi-
dc.contributor.authorAguilar Moncayo, Matilde-
dc.contributor.authorLi, Linjing-
dc.contributor.authorNinomiya, Haruaki-
dc.contributor.authorNanba, Eiji-
dc.contributor.authorOhno, Kousaku-
dc.contributor.authorGarcía Moreno, María Isabel-
dc.contributor.authorOrtiz-Mellet, Carmen-
dc.contributor.authorGarcía-Fernández, José Manuel-
dc.contributor.authorSuzuki, Yoshiyuki-
dc.identifier.citationChemBioChem 11(17): 2453-2464 (2010)es_ES
dc.description12 páginases_ES
dc.description.abstractGaucher 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.es_ES
dc.description.sponsorshipThis research was supported by grants from the Ministry of Education, Culture, Science, Sports, and Technology of Japan (20390297, 13680918, 14207106), the Ministry of Health, Labour and Welfare of Japan (H14-Kokoro-017, H17-Kokoro-019. H20-Kokoro-022 and a grant for Research for Intractable Diseases), the Spanish Ministerio de Ciencia e Innovación (contract numbers CTQ2006-15515-C02-01/BQU and CTQ2007-61180/PPQ), the Junta de Andalucía (Project P08-FQM-03711), the European Union (FEDER) and the Fundación Ramón Areces. M.A.-M. is a FPU fellow.es_ES
dc.subjectFluorescent probeses_ES
dc.subjectGaucher diseasees_ES
dc.titleA Fluorescent sp2-Iminosugar With Pharmacological Chaperone Activity for Gaucher Disease: Synthesis and Intracellular Distribution Studieses_ES
dc.description.peerreviewedPeer reviewedes_ES
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