Iminosugar‐Based Galactoside Mimics as Inhibitors of Galactocerebrosidase: SAR Studies and Comparison with Other Lysosomal Galactosidases

Biela-Banaś, Anna; Oulaïdi, Farah; Front, Sophie; Gallienne, Estelle; Ikeda-Obatake, Kyoko; Asano, Naoki; Wenger, David A.; Martin, Olivier R.

doi:10.1002/cmdc.201402411

Cited by 23 publications

(22 citation statements)

References 44 publications

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“…Following our initial work on pharmacological chaperones for Gaucher disease, we became interested in the application of PCT toward β‐galactosidase‐linked LSDs . As regards GM1‐gangliosidosis, Suzuki et al.…”

Section: Introductionsupporting

confidence: 62%

“…We have recently shown that 1‐ C ‐alkyl DGJ derivatives (Figure ) are quite weak inhibitors of β‐galactosidases, although they are potent inhibitors of α‐galactosidases, including human lysosomal α‐galactosidase . In agreement with Heightman and Vasella′s analysis of glycosidase inhibition by iminosugars, we considered that selective inhibition of β‐galactosidase might arise more effectively from structures in which the basic nitrogen atom occupies the anomeric position in the corresponding galactoside (isofagomine series): 4‐epi‐isofagomine (4‐epi‐IFG, Figure ) is indeed a very potent galactosidase inhibitor .…”

Section: Introductionmentioning

confidence: 99%

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N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

et al. 2015

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A series of 1,5-dideoxy-1,5-imino-(l)-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4-epi-isofagomine (4-epi-IFG) mimics and were expected to behave as selective inhibitors of β-galactosidases. All compounds were indeed found to be highly selective for β-galactosidases versus α-glycosidases, as they generally did not inhibit coffee bean α-galactosidase or other α-glycosidases. Some compounds were also found to be inhibitors of almond β-glucosidase. The N-alkyl DIR derivatives were only modest inhibitors of bovine β-galactosidase, with IC50 values in the 30-700 μM range. Likewise, imino-L-ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced β-galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarkably, the 'pseudo-anomeric' configuration in this series does not appear to play a role. Human lysosomal β-galactosidase from leukocyte lysate was, however, poorly inhibited by all iminoribitol derivatives tested (IC50 values in the 100 μM range), while 4-epi-IFG was a good inhibitor of this enzyme. Two compounds were evaluated as pharmacological chaperones for a GM1-gangliosidosis cell line (R301Q mutation) and were found to enhance the mutant enzyme activity by factors up to 2.7-fold.

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Section: Introductionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

et al. 2015

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“…In the work published to date, a range of different substrates has been used to monitor GALC activity, including tritiated GalCer (Biela‐Banas et al, ), alkylated fluorogenic and colorimetric substrates such as 2‐hexadecanoylamino‐4‐nitrophenyl‐β‐D‐galactopyranoside (HNG; W.C. Lee et al, ) and 6‐hexadecanoylamino‐4‐methylumbelliferyl‐β‐D‐galactopyranoside (HMG; Ribbens et al, ; Berardi et al, ; Hossain et al, ), and water‐soluble fluorogenic and colorimetric substrates such as 4NBDG (Hill et al, ) and 4MBDG (Martino et al, ).…”

Section: Methods For Monitoring the Effectiveness Of Chaperonesmentioning

confidence: 99%

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Spratley

Deane

2016

J of Neuroscience Research

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Missense mutations in the lysosomal hydrolase β‐galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small‐molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

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“…Next, we studied competition of ABP 3 labeling of GALC by two known competitive inhibitors of the enzyme, ABB116 [31] ( Figure 1C, compound 6) and galactosylsphingosine or psychosine ( Figure 1C, compound 7). Labeling of GALC in mouse brain and kidney lysates by probe 3 was fully competed by both inhibitors at millimolar concentration, confirming that the ABP binds to the active site of the enzyme ( Figure 3B).…”

Section: Selectivity Of Galactocerebrosidase Labelingmentioning

confidence: 99%

“…When diagnosed in adolescents or adults other symptoms may be observed such as seizures, feeding difficulties, slowing of mental and motor development, muscle weakness, spasticity, deafness, and blindness. The onset and severity of symptoms as well as the course of the disease in adult Krabbe patients is highly variable, even in patients carrying (6) [31] and galactosylsphingosine (psychosine, 7) are competitive GALC inhibitors. the same mutation.…”

Section: Introductionmentioning

confidence: 99%

A Specific Activity‐Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease

et al. 2017

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Galactosylceramidase (GALC) is the lysosomal β-galactosidase responsible for the hydrolysis of galactosylceramide. Inherited deficiency in GALC causes Krabbe disease, a devastating neurological disorder characterized by accumulation of galactosylceramide and its deacylated counterpart, the toxic sphingoid base galactosylsphingosine (psychosine). We report the design and application of a fluorescently tagged activity-based probe (ABP) for the sensitive and specific labeling of active GALC molecules from various species. The probe consists of a β-galactopyranose-configured cyclophellitol-epoxide core, conferring specificity for GALC, equipped with a Bodipy fluorophore at C6 that allows visualizing active enzyme in cells and tissues. The detection of residual GALC in patient fibroblasts holds great promise for laboratory diagnosis of Krabbe disease. We further describe a procedure for in situ imaging of active GALC in murine brain by intracerebroventricular infusion of the ABP. In conclusion, the GALCspecific ABP should find broad applications in diagnosis, drug development and evaluation of therapy of Krabbe disease.

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Iminosugar‐Based Galactoside Mimics as Inhibitors of Galactocerebrosidase: SAR Studies and Comparison with Other Lysosomal Galactosidases

Cited by 23 publications

References 44 publications

N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

N‐Alkyl‐, 1‐C‐Alkyl‐, and 5‐C‐Alkyl‐1,5‐dideoxy‐1,5‐imino‐(l)‐ribitols as Galactosidase Inhibitors

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

A Specific Activity‐Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease

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