sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
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...
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| Format: | Article |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2073444 |
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| author | 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_facet | 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_sort | Manuel González-Cuesta |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-669c8768aeed4cfeb39c9878c1d290c2 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-669c8768aeed4cfeb39c9878c1d290c22025-08-20T02:36:30ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711364137410.1080/14756366.2022.2073444sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs diseaseManuel González-Cuesta0Irene Herrera-González1M. Isabel García-Moreno2Roger A. Ashmus3David J. Vocadlo4José M. García Fernández5Eiji Nanba6Katsumi Higaki7Carmen Ortiz Mellet8Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, SpainDepartment of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, SpainDepartment of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, SpainDepartment of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, CanadaDepartment of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, CanadaInstituto de Investigaciones Químicas (IIQ), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Sevilla, Sevilla, SpainOrganization for Research Initiative and Promotion, Tottori University, Yonago, JapanOrganization for Research Initiative and Promotion, Tottori University, Yonago, JapanDepartment of Organic Chemistry, Faculty of Chemistry, University of Seville, Sevilla, SpainThe 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.https://www.tandfonline.com/doi/10.1080/14756366.2022.2073444Iminosugarpharmacological chaperonethioureathiazolidineTay-Sachs |
| spellingShingle | 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 sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease Journal of Enzyme Inhibition and Medicinal Chemistry Iminosugar pharmacological chaperone thiourea thiazolidine Tay-Sachs |
| title | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title_full | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title_fullStr | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title_full_unstemmed | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title_short | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title_sort | sp2 iminosugars targeting human lysosomal β hexosaminidase as pharmacological chaperone candidates for late onset tay sachs disease |
| topic | Iminosugar pharmacological chaperone thiourea thiazolidine Tay-Sachs |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2073444 |
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