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

Journal of the American Chemical Society
Marta ArtolaHerman S Overkleeft

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.

References

Feb 1, 1979·Biochimica Et Biophysica Acta·A Hara, N S Radin
Jul 1, 1966·The Journal of Clinical Investigation·R O BradyD Shapiro
Jan 27, 2005·Journal of Inherited Metabolic Disease·U H SchuelerR O Brady
Oct 23, 2009·The New England Journal of Medicine·E SidranskyS G Ziegler
Nov 17, 2010·Nature Chemical Biology·Martin D WitteJohannes M F G Aerts
Sep 29, 2011·Disease Models & Mechanisms·Tamar Farfel-BeckerAnthony H Futerman
Jul 25, 2013·The Journal of Biological Chemistry·Christina M RidleyAarnoud C van der Spoel
Nov 26, 2013·Nucleic Acids Research·Vincent LombardBernard Henrissat
Jan 7, 2015·Journal of the American Chemical Society·Anuj K YadavDavid J Vocadlo
Mar 25, 2015·Molecular and Cellular Neurosciences·Anthony H V Schapira
Apr 27, 2016·ACS Chemical Biology·Ratana CharoenwattanasatienJames R Ketudat Cairns
May 29, 2016·The Journal of Pathology·Ayelet VardiAnthony H Futerman
Jan 8, 2018·Methods in Enzymology·Chi-Lin KuoJohannes Maria Aerts

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Citations

Aug 23, 2020·Cells·Maria Teresa ValentiLuca Dalle Carbonare
Apr 23, 2020·Frontiers in Plant Science·Kassiani KytidouJohannes M F G Aerts
Mar 19, 2020·Journal of Clinical Medicine·Daphne E C BoerJohannes M F G Aerts
Sep 29, 2019·Journal of Lipid Research·Lindsey T LelieveldJohannes M F G Aerts
Sep 26, 2020·Biomolecules·Maximilian Breuer, Shunmoogum A Patten
Jun 5, 2020·Acta Crystallographica. Section D, Structural Biology·Rhianna J RowlandGideon J Davies
Aug 17, 2019·Current Opinion in Chemical Biology·Liang WuGideon J Davies
Aug 31, 2021·Chembiochem : a European Journal of Chemical Biology·Qin SuChi-Lin Kuo
Sep 28, 2021·Chemistry : a European Journal·Rhianna J RowlandGideon J Davies

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