Glucosylceramide Mimics: Highly Potent GCase Inhibitors and Selective Pharmacological Chaperones for Mutations Associated with Types 1 and 2 Gaucher Disease
PBN-AR
Instytucja
Instytut Chemii Organicznej Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
en
Czasopismo
ChemMedChem
ISSN
1860-7179
EISSN
1860-7187
Wydawca
WILEY-BLACKWELL
DOI
URL
Rok publikacji
2013
Numer zeszytu
11
Strony od-do
1805-1817
Numer tomu
8
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
en
Gaucher disease
glycolipids
glycosidase inhibitors
iminosugars
pharmacological chaperones
Streszczenia
Język
en
Treść
A series of iminoxylitol derivatives carrying a C-linked di-O-acyl or di-O-alkyl glyceryl substituent were prepared and characterized. All of these compounds, which were designed as glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal β-glucosidase (glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di-O-hexyl ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di-O-decanoyl ester was a potent chaperone of the L444P hydrolase, capable of increasing the residual activity of the enzyme by a factor of two at a very low concentration (50 nM); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat-stress studies, the diether was found to be much more effective in stabilizing the wild-type enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of GlcCer synthase, because such compounds could find use in the substrate reduction therapy approach to treat lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di-C10-ester constitute leads for the development of therapeutic agents for types 2 and 3 Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.
Cechy publikacji
ORIGINAL_ARTICLE
Inne
System-identifier
648949
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