Functionalized Cyclophellitols Are Selective Glucocerebrosidase Inhibitors and Induce a Bona Fide Neuropathic Gaucher Model in Zebrafish.
J Am Chem Soc
; 141(10): 4214-4218, 2019 03 13.
Article
en En
| MEDLINE
| ID: mdl-30811188
ABSTRACT
Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining ß-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ciclohexanoles
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Proteínas de Pez Cebra
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Modelos Animales de Enfermedad
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Inhibidores Enzimáticos
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Enfermedad de Gaucher
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Glucosilceramidasa
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2019
Tipo del documento:
Article