Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease
The synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactos...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/176972 |
| Acceso en línea: | https://hdl.handle.net/11441/176972 https://doi.org/10.1016/j.ejmech.2020.112173 |
| Access Level: | acceso abierto |
| Palabra clave: | Iminosugars Multivalency Glycosidases α-galactosidase inhibitors βglucocerebrosidase inhibitors Pharmacological chaperones |
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Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry diseaseMartínez Bailén, MacarenaCarmona Asenjo, Ana TeresaCardona, FrancescaMatassini, CamillaGoti, AndreaKubo, MoemiKato, AtsushiRobina Ramírez, InmaculadaMoreno Vargas, Antonio JoséIminosugarsMultivalencyGlycosidasesα-galactosidase inhibitorsβglucocerebrosidase inhibitorsPharmacological chaperonesThe synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactosidase A (α-Gal A) and lysosomal β-glucocerebrosidase (GCase). Structure-activity relationships were established focusing on the iminosugar inhitope, the valency of the dendron and the linker between the inhitope and the central scaffold. Remarkable is the result obtained in the inhibition of α-Gal A, where one of the nonavalent compounds showed potent inhibition (0.20 μM, competitive inhibition), being a 375-fold more potent inhibitor than the monovalent reference. The potential of the best α-Gal A inhibitors to act as pharmacological chaperones was analyzed by evaluating their ability to increase the activity of this enzyme in R301G fibroblasts from patients with Fabry disease, a genetic disorder related with a reduced activity of α-Gal A. The best enzyme activity enhancement was obtained for the same nonavalent compound, which increased 5.2-fold the activity of the misfolded enzyme at 2.5 μM, what constitutes the first example of a multivalent α-Gal A activity enhancer of potential interest in the treatment of Fabry disease.ElsevierQuímica OrgánicaMinisterio de Economía y Competitividad (MINECO). EspañaJunta de AndalucíaJapanese Society for the Promotion of ScienceEnte Cassa di Risparmio di Firenze2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/176972https://doi.org/10.1016/j.ejmech.2020.112173reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésEuropean Journal of Medicinal Chemistry, 192, 112173.CTQ2016-77270-RFQM-345JP17K083622016/08452018.0942https://doi.org/10.1016/j.ejmech.2020.112173info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1769722026-06-17T12:51:07Z |
| dc.title.none.fl_str_mv |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| title |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| spellingShingle |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease Martínez Bailén, Macarena Iminosugars Multivalency Glycosidases α-galactosidase inhibitors βglucocerebrosidase inhibitors Pharmacological chaperones |
| title_short |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| title_full |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| title_fullStr |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| title_full_unstemmed |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| title_sort |
Synthesis of multimeric pyrrolidine iminosugar inhibitors of human β-glucocerebrosidase and α-galactosidase A: First example of a multivalent enzyme activity enhancer for Fabry disease |
| dc.creator.none.fl_str_mv |
Martínez Bailén, Macarena Carmona Asenjo, Ana Teresa Cardona, Francesca Matassini, Camilla Goti, Andrea Kubo, Moemi Kato, Atsushi Robina Ramírez, Inmaculada Moreno Vargas, Antonio José |
| author |
Martínez Bailén, Macarena |
| author_facet |
Martínez Bailén, Macarena Carmona Asenjo, Ana Teresa Cardona, Francesca Matassini, Camilla Goti, Andrea Kubo, Moemi Kato, Atsushi Robina Ramírez, Inmaculada Moreno Vargas, Antonio José |
| author_role |
author |
| author2 |
Carmona Asenjo, Ana Teresa Cardona, Francesca Matassini, Camilla Goti, Andrea Kubo, Moemi Kato, Atsushi Robina Ramírez, Inmaculada Moreno Vargas, Antonio José |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Química Orgánica Ministerio de Economía y Competitividad (MINECO). España Junta de Andalucía Japanese Society for the Promotion of Science Ente Cassa di Risparmio di Firenze |
| dc.subject.none.fl_str_mv |
Iminosugars Multivalency Glycosidases α-galactosidase inhibitors βglucocerebrosidase inhibitors Pharmacological chaperones |
| topic |
Iminosugars Multivalency Glycosidases α-galactosidase inhibitors βglucocerebrosidase inhibitors Pharmacological chaperones |
| description |
The synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactosidase A (α-Gal A) and lysosomal β-glucocerebrosidase (GCase). Structure-activity relationships were established focusing on the iminosugar inhitope, the valency of the dendron and the linker between the inhitope and the central scaffold. Remarkable is the result obtained in the inhibition of α-Gal A, where one of the nonavalent compounds showed potent inhibition (0.20 μM, competitive inhibition), being a 375-fold more potent inhibitor than the monovalent reference. The potential of the best α-Gal A inhibitors to act as pharmacological chaperones was analyzed by evaluating their ability to increase the activity of this enzyme in R301G fibroblasts from patients with Fabry disease, a genetic disorder related with a reduced activity of α-Gal A. The best enzyme activity enhancement was obtained for the same nonavalent compound, which increased 5.2-fold the activity of the misfolded enzyme at 2.5 μM, what constitutes the first example of a multivalent α-Gal A activity enhancer of potential interest in the treatment of Fabry disease. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/11441/176972 https://doi.org/10.1016/j.ejmech.2020.112173 |
| url |
https://hdl.handle.net/11441/176972 https://doi.org/10.1016/j.ejmech.2020.112173 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
European Journal of Medicinal Chemistry, 192, 112173. CTQ2016-77270-R FQM-345 JP17K08362 2016/0845 2018.0942 https://doi.org/10.1016/j.ejmech.2020.112173 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
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reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US) |
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Universidad de Sevilla (US) |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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