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...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/138556 |
| Acceso en línea: | https://hdl.handle.net/11441/138556 https://doi.org/10.1080/14756366.2022.2073444 |
| Access Level: | acceso abierto |
| Palabra clave: | Iminosugar Pharmacological chaperone Thiourea Thiazolidine Tay-Sachs |
| id |
ES_fed69ec5f658496dcf778ffefeb662a8 |
|---|---|
| oai_identifier_str |
oai:idus.us.es:11441/138556 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs diseaseGonzález Cuesta, ManuelHerrera González, IreneGarcía Moreno, M. IsabelAshmus, Roger A.Vocadlo, David J.García Fernández, José ManuelNanba, EijiHigaki, KatsumiOrtiz Mellet, CarmenIminosugarPharmacological chaperoneThioureaThiazolidineTay-SachsThe 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.Ministerio de Ciencia e Innovación 10.13039/50110001103Fondo Europeo de Desarrollo Regional PID2019-105858RB-I00, RTI2018-097609-B-C21Junta de Andalucía P20_00166Canadian Institutes of Health Research MOP-123341Natural Sciences and Engineering Research Council of Canada RGPIN-06466Japan Society for the Promotion of Science 17K10051Universidad de Sevilla BES-2017–079676, FPU17/03147Taylor & FrancisQuímica OrgánicaMinisterio de Ciencia e Innovación (MICIN). EspañaFondo Europeo de Desarrollo Regional (FEDER)Junta de AndalucíaCanadian Institutes of Health ResearchNatural Sciences and Engineering Research Council of Canada (NSERC)Japan Society for the Promotion of ScienceUniversidad de Sevilla2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/138556https://doi.org/10.1080/14756366.2022.2073444reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésJournal of Enzyme Inhibition and Medicinal Chemistry, 37 (1), 1364 - 1374.10.13039/50110001103PID2019-105858RB-I00RTI2018-097609-B-C21P20_00166MOP-123341RGPIN-0646617K10051BES-2017–079676FPU17/03147https://doi.org/10.1080/14756366.2022.2073444info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1385562026-06-17T12:51:07Z |
| dc.title.none.fl_str_mv |
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| title |
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| spellingShingle |
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease González Cuesta, Manuel Iminosugar Pharmacological chaperone Thiourea Thiazolidine Tay-Sachs |
| title_short |
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_sort |
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease |
| dc.creator.none.fl_str_mv |
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 |
| author |
González Cuesta, Manuel |
| author_facet |
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 |
| author_role |
author |
| author2 |
Herrera González, Irene García Moreno, M. Isabel Ashmus, Roger A. Vocadlo, David J. García Fernández, José Manuel Nanba, Eiji Higaki, Katsumi Ortiz Mellet, Carmen |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Química Orgánica 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 |
| dc.subject.none.fl_str_mv |
Iminosugar Pharmacological chaperone Thiourea Thiazolidine Tay-Sachs |
| topic |
Iminosugar Pharmacological chaperone Thiourea Thiazolidine Tay-Sachs |
| 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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/11441/138556 https://doi.org/10.1080/14756366.2022.2073444 |
| url |
https://hdl.handle.net/11441/138556 https://doi.org/10.1080/14756366.2022.2073444 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Journal of Enzyme Inhibition and Medicinal Chemistry, 37 (1), 1364 - 1374. 10.13039/50110001103 PID2019-105858RB-I00 RTI2018-097609-B-C21 P20_00166 MOP-123341 RGPIN-06466 17K10051 BES-2017–079676 FPU17/03147 https://doi.org/10.1080/14756366.2022.2073444 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Taylor & Francis |
| publisher.none.fl_str_mv |
Taylor & Francis |
| dc.source.none.fl_str_mv |
reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US) |
| instname_str |
Universidad de Sevilla (US) |
| reponame_str |
idUS. Depósito de Investigación de la Universidad de Sevilla |
| collection |
idUS. Depósito de Investigación de la Universidad de Sevilla |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869425720494653440 |
| score |
15.301629 |