Artículo
sp2-Iminosugar Azobenzene O-glycosides: Light-sensitive Glycosidase Inhibitors with Unprecedented Tunability and Switching Factors
Autor/es | Rivero Barbarroja, Gonzalo
Padilla Pérez, María del Carmen ![]() ![]() ![]() ![]() ![]() ![]() Maisonneuve, Stéphane García Moreno, M. Isabel ![]() ![]() ![]() ![]() ![]() ![]() Tiet, Ben Vocadlo, David J. Xie, Juan García Fernández, José M. Ortiz Mellet, Carmen ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2024 |
Fecha de depósito | 2024-06-24 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia, Innovación y Universidades (MICINN). España European Cooperation in Science and Technology (COST) Natural Sciences and Engineering Research Council of Canada (NSERC) Universidad de Sevilla |
Identificador del proyecto | PID2022-141034OB-C21
![]() PID2021-124247OB-C21 ![]() CM18132 ![]() RGPIN-2020-06466 ![]() FPU18/02922 ![]() FPU19/04361 ![]() |
Cita | 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. |
Ficheros | Tamaño | Formato | Ver | Descripción |
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sp2-Iminosugar azobenzene ... | 1011.Kb | ![]() | Ver/ | |