dc.creator | Rivero Barbarroja, Gonzalo | es |
dc.creator | Padilla Pérez, María del Carmen | es |
dc.creator | Maisonneuve, Stéphane | es |
dc.creator | García Moreno, M. Isabel | es |
dc.creator | Tiet, Ben | es |
dc.creator | Vocadlo, David J. | es |
dc.creator | Xie, Juan | es |
dc.creator | García Fernández, José M. | es |
dc.creator | Ortiz Mellet, Carmen | es |
dc.date.accessioned | 2024-06-24T13:22:43Z | |
dc.date.available | 2024-06-24T13:22:43Z | |
dc.date.issued | 2024 | |
dc.identifier.citation | Rivero Barbarroja, G., Padilla Pérez, M.d.C., Maisonneuve, S., García Moreno, M.I., Tiet, B., Vocadlo, D.J.,...,Ortiz Mellet, C. (2024). sp2-Iminosugar Azobenzene O-glycosides: Light-sensitive Glycosidase Inhibitors with Unprecedented Tunability and Switching Factors. Bioorganic Chemistry, 150, 107555. https://doi.org/10.1016/j.bioorg.2024.107555. | |
dc.identifier.issn | 0045-2068 | es |
dc.identifier.issn | 1090-2120 | es |
dc.identifier.uri | https://hdl.handle.net/11441/160818 | |
dc.description.abstract | The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and β-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human β-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and β-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach. | es |
dc.description.sponsorship | Ministerio de Ciencia, Innovación y Universidades PID2021-124247OB-C21, PID2022-141034OB-C21 | es |
dc.description.sponsorship | European Cooperation in Science and Technology CM18132 | es |
dc.description.sponsorship | Natural Sciences and Engineering Research Council of Canada RGPIN-2020-06466 | es |
dc.description.sponsorship | Universidad de Sevilla FPU18/02922, FPU19/04361 | es |
dc.format | application/pdf | es |
dc.format.extent | 8 p. | es |
dc.language.iso | eng | es |
dc.publisher | Elsevier | es |
dc.relation.ispartof | Bioorganic Chemistry, 150, 107555. | |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Azobenzene | es |
dc.subject | Glycosidase inhibitors | es |
dc.subject | Photoswitchers | es |
dc.subject | sp2-Iminosugars | es |
dc.subject | β-glucocerebrosidase | es |
dc.title | sp2-Iminosugar Azobenzene O-glycosides: Light-sensitive Glycosidase Inhibitors with Unprecedented Tunability and Switching Factors | es |
dc.type | info:eu-repo/semantics/article | es |
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 | PID2022-141034OB-C21 | es |
dc.relation.projectID | PID2021-124247OB-C21 | es |
dc.relation.projectID | CM18132 | es |
dc.relation.projectID | RGPIN-2020-06466 | es |
dc.relation.projectID | FPU18/02922 | es |
dc.relation.projectID | FPU19/04361 | es |
dc.relation.publisherversion | https://doi.org/10.1016/j.bioorg.2024.107555 | es |
dc.identifier.doi | 10.1016/j.bioorg.2024.107555 | es |
dc.journaltitle | Bioorganic Chemistry | es |
dc.publication.volumen | 150 | es |
dc.publication.initialPage | 107555 | es |
dc.contributor.funder | Ministerio de Ciencia, Innovación y Universidades (MICINN). España | es |
dc.contributor.funder | European Cooperation in Science and Technology (COST) | es |
dc.contributor.funder | Natural Sciences and Engineering Research Council of Canada (NSERC) | es |
dc.contributor.funder | Universidad de Sevilla | es |