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sp²-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease.
- Source :
- Journal of Enzyme Inhibition & Medicinal Chemistry; 2022, Vol. 37 Issue 1, p1364-1374, 11p
- Publication Year :
- 2022
-
Abstract
- The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp²-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning. They increased the levels of lysosomal HexA activity in Tay-Sachs patient fibroblasts having the G269S mutation, the highest prevalent in late-onset Tay-Sachs disease. [ABSTRACT FROM AUTHOR]
- Subjects :
- THIOUREA
HUMAN beings
MOLECULAR chaperones
ENZYMES
FIBROBLASTS
Subjects
Details
- Language :
- English
- ISSN :
- 14756366
- Volume :
- 37
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Enzyme Inhibition & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 161132797
- Full Text :
- https://doi.org/10.1080/14756366.2022.2073444