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Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish
Authors:
Marta
Artola
(Leiden University)
,
Chi-lin
Kuo
(Leiden University)
,
Lindsey T.
Lelieveld
(Leiden University)
,
Rhianna J.
Rowland
(University of York)
,
Gijsbert A.
Van Der Marel
(Leiden University)
,
Jeroen D. C.
Codée
(Leiden University)
,
Rolf G.
Boot
(Leiden University)
,
Gideon J.
Davies
(University of York)
,
Johannes M. F. G.
Aerts
(Leiden University)
,
Herman S.
Overkleeft
(Leiden University)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of The American Chemical Society
State:
Published (Approved)
Published:
March 2019
Diamond Proposal Number(s):
13587

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 generation 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.
Subject Areas:
Biology and Bio-materials,
Chemistry
Instruments:
I02-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Documents:
465rtgrt56.pdf