Artículo
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Autor/es | González Cuesta, Manuel
Herrera González, Irene García Moreno, M. Isabel Ashmus, Roger A. Vocadlo, David J. García Fernández, José Manuel Nanba, Eiji Higaki, Katsumi Ortiz Mellet, Carmen |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-10-31 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Fondo Europeo de Desarrollo Regional (FEDER) Junta de Andalucía Canadian Institutes of Health Research Natural Sciences and Engineering Research Council of Canada (NSERC) Japan Society for the Promotion of Science Universidad de Sevilla |
Identificador del proyecto | 10.13039/50110001103
PID2019-105858RB-I00 RTI2018-097609-B-C21 P20_00166 MOP-123341 RGPIN-06466 17K10051 BES-2017–079676 FPU17/03147 |
Cita | González Cuesta, M., Herrera González, I., García Moreno, M.I., Ashmus, R.A., Vocadlo, D.J., García Fernández, J.M.,...,Ortiz Mellet, C. (2022). sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease. Journal of Enzyme Inhibition and Medicinal Chemistry, 37 (1), 1364 - 1374. https://doi.org/10.1080/14756366.2022.2073444. |
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