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)

Keywords
Authors
  • 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.

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