PUBLICATION

Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Authors
Artola, M., Kuo, C.L., Lelieveld, L.T., Rowland, R.J., van der Marel, G.A., Codée, J.D.C., Boot, R.G., Davies, G.J., Aerts, J.M.F.G., Overkleeft, H.S.
ID
ZDB-PUB-190228-5
Date
2019
Source
Journal of the American Chemical Society   141(10): 4214-4218 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Cyclohexanols/pharmacology*
  • Disease Models, Animal*
  • Enzyme Inhibitors/pharmacology*
  • Gaucher Disease/chemically induced*
  • Glucosylceramidase/antagonists & inhibitors*
  • Humans
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors*
PubMed
30811188 Full text @ J. Am. Chem. Soc.
Abstract
Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE) and cyclophellitol. Both compounds however also target other retaining glycosidases, rendering genera-tion and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping