sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 37 (2022)
- Manuel González-Cuesta
- Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, Spain
- Irene Herrera-González
- Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, Spain
- M. Isabel García-Moreno
- Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, Spain
- Roger A. Ashmus
- Department of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada
- David J. Vocadlo
- Department of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada
- José M. García Fernández
- Instituto de Investigaciones Químicas (IIQ), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Sevilla, Sevilla, Spain
- Eiji Nanba
- Organization for Research Initiative and Promotion, Tottori University, Yonago, Japan
- Katsumi Higaki
- Organization for Research Initiative and Promotion, Tottori University, Yonago, Japan
- Carmen Ortiz Mellet
- Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, Spain
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.