sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

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...

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Bibliographic Details
Published in:Journal of Enzyme Inhibition and Medicinal Chemistry
Main Authors: Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
Format: Article
Language:English
Published: Taylor & Francis Group 2022-12-01
Subjects:
Iminosugar
pharmacological chaperone
thiourea
thiazolidine
Tay-Sachs
Online Access:https://www.tandfonline.com/doi/10.1080/14756366.2022.2073444
Description
Summary: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.
ISSN:1475-6366
1475-6374

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