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

Marta Artola, Chi-Lin Kuo, Lindsey T. Lelieveld, Rhianna J. Rowland, Gijsbert A. van der Marel, Jeroen D. C. Codée, Rolf G. Boot, Gideon J. Davies, Johannes M. F. G. Aerts, Herman S. Overkleeft

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to) 4214–4218
Number of pages5
JournalJournal of the American Chemical Society
Issue number10
Early online date27 Feb 2019
Publication statusPublished - 13 Mar 2019

Bibliographical note

© 2019 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

Cite this