GONZALEZ CUESTA, MANUEL, Herrera-Gonzalez, Irene , Garcia-Moreno, M. Isabel , Ashmus, Roger A. , Vocadlo, David J. , Garcia Fernandez, Jose M. , Nanba, Eiji , Higaki, Katsumi , Ortiz Mellet, Carmen
No
J. Enzym. Inhib. Med. Chem.
Article
Científica
1
2
5.6
0.814
31/12/2022
000796253300001
The late-onset form of Tay-Sachs disease displays when the activity levels of human beta-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 sp(2)-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.
Iminosugar; pharmacological chaperone; thiourea; thiazolidine; Tay-Sachs