Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Hill, C.P.; Viuff, Agnete H.; Spratley, Samantha J.; Salamone, Stéphane; Christensen, Stig H.; Read, Randy J.; Moriarty, Nigel W.; Jensen, Henrik H.; Deane, Janet E.

doi:10.1039/c5sc00754b

Cited by 44 publications

(39 citation statements)

References 87 publications

(106 reference statements)

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“…Thus, for this mutation, the chaperoning effect conferred by α‐lobeline might have been specific to the newly introduced glycan. In support of this, it was observed that α‐lobeline does not confer any increase in thermal stability to WT GALC and may also explain why it did not have a chaperoning effect on the other GALC variants tested (W.C. Lee et al, ; Hill et al, ).…”

Section: Identifying Candidate Mutations For Pctmentioning

confidence: 89%

“…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%

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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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Section: Identifying Candidate Mutations For Pctmentioning

confidence: 89%

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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“…Under chemical profile, azasugars and iminosugars were tested as GALC inhibitors and as PCs. Specifically, Hill and coworkers () identified some chemical characteristics that, associated with azasugar compound, are required for PC specificity and pH‐dependent affinity for GALC. This work was made possible by recent studies on not only the structures of GALC but also the mode of binding of substrate, intermediate, and product to the enzyme active site, accompanied by conformational changes of active site residues (Deane et al, ; Hill et al, ).…”

Section: Chaperones For Kd: Preclinical Studiesmentioning

confidence: 99%

Chaperones as potential therapeutics for Krabbe disease

Graziano

Pannuzzo

Avola

et al. 2016

J of Neuroscience Research

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Krabbe's disease (KD) is an autosomal recessive, neurodegenerative disorder. It is classified among the lysosomal storage diseases (LSDs). It was first described in , but the genetic defect for the galactocerebrosidase (GALC) gene was not discovered until the beginning of the 1970s, 20 years before the GALC cloning. Recently, in 2011, the crystal structures of the GALC enzyme and the GALC-product complex were obtained. For this, compared with other LSDs, the research on possible therapeutic interventions is much more recent. Thus, it is not surprising that some treatment options are still under preclinical investigation, whereas their relevance for other pathologies of the same group has already been tested in clinical studies. This is specifically the case for pharmacological chaperone therapy (PCT), a promising strategy for selectively correcting defective protein folding and trafficking and for enhancing enzyme activity by small molecules. These compounds bind directly to a partially folded biosynthetic intermediate, stabilize the protein, and allow completion of the folding process to yield a functional protein. Here, we review the chaperones that have demonstrated potential therapeutics during preclinical studies for KD, underscoring the requirement to invigorate research for KD-addressed PCT that will benefit from recent insights into the molecular understanding of GALC structure, drug design, and development in cellular models. © 2016 Wiley Periodicals, Inc.

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“…oryzae, o-nitrophenyl β-D-galactopyranoside for β-galactosidase from E. coli, p-nitrophenyl β-D-glucopyranoside for almond β-glucosidase, p-nitrophenyl α-D-glucopyranoside for yeast α-glucosidase and p-nitrophenyl α-D-galactopyranoside for green coffee beans α-galactosidase) at six concentrations ranging from 1/4K m up to 4 K m monitoring at 400 nm with A < 1 using a Varian Cary 100 Bio UV-vis spectrophotometer. Methyl 3,4-di-O-benzyl-2-benzyloxymethyl-2-deoxy-α/β-D-allopyranoside (14). For experiments with preincubation, enzyme and inhibitor were mixed 30 min prior to addition of substrate.…”

Section: Inhibition Studiesmentioning

confidence: 99%

Synthesis and evaluation of galacto-noeurostegine and its 2-deoxy analogue as glycosidase inhibitors

et al. 2015

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An epimer of the known glycosidase inhibitor noeurostegine, galacto-noeurostegine, was synthesised in 21 steps from levoglucosan and found to be a potent, competitive and highly selective galactosidase inhibitor of Aspergillus oryzae β-galactosidase. Galacto-noeurostegine was not found to be an inhibitor of green coffee bean α-galactosidase, yeast α-glucosidase and E. coli β-galactosidase, whereas potent but non-competitive inhibition against sweet almond β-glucosidase was established. The 2-deoxy-galacto-noeurostegine analogue was also prepared and found to be a less potent inhibitor of the same enzymes.

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Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Abstract: Modified azasugar molecules have been synthesized and characterized as excellent pharmacological chaperone candidates to treat the neurodegenerative disorder Krabbe disease.

Cited by 44 publications

References 87 publications

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

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

Chaperones as potential therapeutics for Krabbe disease

Synthesis and evaluation of galacto-noeurostegine and its 2-deoxy analogue as glycosidase inhibitors

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