Download MendeleyFunctionalized Cyclophellitols Are Selective Glucocerebrosidase Inhibitors and Induce a Bona Fide Neuropathic Gaucher Model in Zebrafish.
Artola, M., Kuo, C.L., Lelieveld, L.T., Rowland, R.J., van der Marel, G.A., Codee, J.D.C., Boot, R.G., Davies, G.J., Aerts, J.M.F.G., Overkleeft, H.S.(2019) J Am Chem Soc 141: 4214-4218
- PubMed: 30811188
- DOI: https://doi.org/10.1021/jacs.9b00056
- Primary Citation of Related Structures:
6Q6K, 6Q6L, 6Q6N - PubMed Abstract:
Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining ¦Â-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.
Organizational Affiliation:
Department of Chemistry, York Structural Biology Laboratory , University of York , Heslington, York YO10 5DD , United Kingdom.
