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Functionalized Cyclophellitols Are Selective Glucocerebrosidase Inhibitors and Induce a Bona Fide Neuropathic Gaucher Model in Zebrafish

Lookup NU author(s): Rhianna RowlandORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

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.

Publication metadata

Author(s): Artola M, Kuo CL, Lelieveld LT, Rowland RJ, van der Marel GA, Codee JDC, Boot RG, Davies GJ, Aerts JMFG, Overkleeft HS

Publication type: Article

Publication status: Published

Journal: Journal of the American Chemical Society

Year: 2019

Volume: 141

Issue: 10

Pages: 4214-4218

Print publication date: 13/03/2019

Online publication date: 27/02/2019

Acceptance date: 02/04/2018

Date deposited: 24/01/2022

ISSN (print): 0002-7863

ISSN (electronic): 1520-5126

Publisher: American Chemical Society

URL: https://doi.org/10.1021/jacs.9b00056

DOI: 10.1021/jacs.9b00056

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