α-1-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease

Yu, Liang; Ikeda, Kyoko; Kato, Atsushi; Adachi, Isao; Godin, Guillaume; Compain, Philippe; Martin, Olivier R.; Asano, Naoki

doi:10.1016/j.bmc.2006.08.003

Cited by 103 publications

(104 citation statements)

References 27 publications

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“…2A). Interestingly, there is a Ͼ300-fold difference in the K i values of the two inhibitors (116 M for NB-DNJ and 0.3 M for NN-DNJ) (27), which cannot be accounted for by this one additional contact. Rather, the lower K i of NN-DNJ is most likely a reflection of the increased overall hydrophobicity of NN-DNJ compared with NB-DNJ (Table 3), with the hydrophobic surface at the entrance to the active site favoring the more hydrophobic ligand.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid β-Glucosidase

Brumshtein

Greenblatt

Butters

et al. 2007

Journal of Biological Chemistry

113

135

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Gaucher disease is caused by mutations in the gene encoding acid ␤-glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently available orally administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavesca TM , NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration than that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2 Å resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino sugar moiety making hydrogen bonds to side chains of active site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented toward the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu-340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars.

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Section: Resultsmentioning

confidence: 99%

Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid β-Glucosidase

Brumshtein

Greenblatt

Butters

et al. 2007

Journal of Biological Chemistry

113

135

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“…Although only a small number of proteins were included in the present study, they represented proteins that use similar trafficking pathways as CFTR (hERG, G601S-hERG) or are from the same superfamily as CFTR (G268V-P-gp, Y490del-P-gp), as well as other ER-arrested misfolded proteins that likely use chaperone pathways distinct from CFTR (α1-ATZ and N370S-β-glucosidase) (36)(37)(38)(39). The effect of VX-809 on F508del-CFTR and Corr-4a and VRT-325 on F508del-CFTR and other mutant proteins was greater than that observed for the normal protein forms.…”

Section: Discussionmentioning

confidence: 99%

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Goor

Hadida

Grootenhuis

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

973

985

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC 50 , 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

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“…In this approach, the chaperone compound binds reversibly to the mutant enzyme, stabilizing its structure and restoring proper trafficking to the lysosome, and then dissociates, allowing the enzyme to metabolize the accumulated substrate. Current efforts to develop small molecule chaperone therapies for Gaucher disease have focused primarily on iminosugar GC substrate analogs (17)(18)(19)(20)(21)(22). However, these molecules can inhibit other glycolipid and glycoprotein processing enzymes and many have fairly low potency and brief half-lives (14,16,26).…”

Section: Discussionmentioning

confidence: 99%

“…The hypothesized mechanism of action for these compounds is competitive binding to the active site of the mutant enzyme, facilitating proper folding and trafficking to the lysosome, where endogenous substrate displaces the chaperone and enzyme activity is restored (8,13,15). Most GC chaperones studied to date are enzyme inhibitors in the structural class of iminosugars or similar analogs of the natural substrate, glucosylceramide (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Iminosugars have been shown to increase the cellular activity of the N370S mutant form of GC, as well as of wild-type enzyme (15,26).…”

mentioning

confidence: 99%

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Zheng

Padia

Urban

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

137

130

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Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structureactivity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40 -90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders.probe identification ͉ structure-activity relationship ͉ small-molecule inhibitor ͉ chaperone therapy

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α-1-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease

Cited by 103 publications

References 27 publications

Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid β-Glucosidase

Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid β-Glucosidase

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

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