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
em 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
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cicloexanóis
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Proteínas de Peixe-Zebra
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Modelos Animais de Doenças
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Inibidores Enzimáticos
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Doença de Gaucher
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Glucosilceramidase
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2019
Tipo de documento:
Article