sp-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease.
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
Author Information
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. ORCID
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. ORCID
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.
