sp 2 -Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

• Published in: Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.1364-1374
• Main Authors: González-Cuesta, Manuel, Herrera-González, Irene, García-Moreno, M Isabel, Ashmus, Roger A, Vocadlo, David J, García Fernández, José M, Nanba, Eiji, Higaki, Katsumi, Ortiz Mellet, Carmen
• Format: Article
• Language: English
• Subjects: beta-N-Acetylhexosaminidases; Hexosaminidase A - genetics; Humans; Lysosomes; Piperidines; Tay-Sachs Disease - drug therapy; Tay-Sachs Disease - genetics
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2073444

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 sp -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.