dc.creator | González Cuesta, Manuel | es |
dc.creator | Herrera González, Irene | es |
dc.creator | García Moreno, M. Isabel | es |
dc.creator | Ashmus, Roger A. | es |
dc.creator | Vocadlo, David J. | es |
dc.creator | García Fernández, José Manuel | es |
dc.creator | Nanba, Eiji | es |
dc.creator | Higaki, Katsumi | es |
dc.creator | Ortiz Mellet, Carmen | es |
dc.date.accessioned | 2022-10-31T18:58:38Z | |
dc.date.available | 2022-10-31T18:58:38Z | |
dc.date.issued | 2022 | |
dc.identifier.citation | 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. | |
dc.identifier.issn | 1475-6366 | es |
dc.identifier.issn | 1475-6374 | es |
dc.identifier.uri | https://hdl.handle.net/11441/138556 | |
dc.description.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. | es |
dc.description.sponsorship | Ministerio de Ciencia e Innovación 10.13039/50110001103 | es |
dc.description.sponsorship | Fondo Europeo de Desarrollo Regional PID2019-105858RB-I00, RTI2018-097609-B-C21 | es |
dc.description.sponsorship | Junta de Andalucía P20_00166 | es |
dc.description.sponsorship | Canadian Institutes of Health Research MOP-123341 | es |
dc.description.sponsorship | Natural Sciences and Engineering Research Council of Canada RGPIN-06466 | es |
dc.description.sponsorship | Japan Society for the Promotion of Science 17K10051 | es |
dc.description.sponsorship | Universidad de Sevilla BES-2017–079676, FPU17/03147 | es |
dc.format | application/pdf | es |
dc.format.extent | 12 p. | es |
dc.language.iso | eng | es |
dc.publisher | Taylor & Francis | es |
dc.relation.ispartof | Journal of Enzyme Inhibition and Medicinal Chemistry, 37 (1), 1364 - 1374. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Iminosugar | es |
dc.subject | Pharmacological chaperone | es |
dc.subject | Thiourea | es |
dc.subject | Thiazolidine | es |
dc.subject | Tay-Sachs | es |
dc.title | sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Química orgánica | es |
dc.relation.projectID | 10.13039/50110001103 | es |
dc.relation.projectID | PID2019-105858RB-I00 | es |
dc.relation.projectID | RTI2018-097609-B-C21 | es |
dc.relation.projectID | P20_00166 | es |
dc.relation.projectID | MOP-123341 | es |
dc.relation.projectID | RGPIN-06466 | es |
dc.relation.projectID | 17K10051 | es |
dc.relation.projectID | BES-2017–079676 | es |
dc.relation.projectID | FPU17/03147 | es |
dc.relation.publisherversion | https://doi.org/10.1080/14756366.2022.2073444 | es |
dc.identifier.doi | 10.1080/14756366.2022.2073444 | es |
dc.journaltitle | Journal of Enzyme Inhibition and Medicinal Chemistry | es |
dc.publication.volumen | 37 | es |
dc.publication.issue | 1 | es |
dc.publication.initialPage | 1364 - 1374 | es |
dc.contributor.funder | Ministerio de Ciencia e Innovación (MICIN). España | es |
dc.contributor.funder | Fondo Europeo de Desarrollo Regional (FEDER) | es |
dc.contributor.funder | Junta de Andalucía | es |
dc.contributor.funder | Canadian Institutes of Health Research | es |
dc.contributor.funder | Natural Sciences and Engineering Research Council of Canada (NSERC) | es |
dc.contributor.funder | Japan Society for the Promotion of Science | es |
dc.contributor.funder | Universidad de Sevilla | es |