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

DOI: 10.1021/jacs.9b00056 DOI Help

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

Open Access Open Access

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


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