Artículo
A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM1 Gangliosidosis
Autor/es | Takai, Tomoko
Higaki, Katsumi Aguilar Moncayo, Matilde Mena Barragán, Teresa Hirano, Yuki Yura, Kei García Moreno, M. Isabel Ortiz Mellet, Carmen García Fernández, José Manuel Suzuki, Yoshiyuki |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2013 |
Fecha de depósito | 2022-05-31 |
Publicado en |
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Resumen | Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands ... Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of β-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp2-iminosugar type, namely 5N,6S-(N′-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant β-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human β-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N′-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 β-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of β-Gal mutants. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Fundación Ramón Areces Junta de Andalucía European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) European Commission. Fondo Social Europeo (FSO) |
Identificador del proyecto | SAF2010-15670
CTQ2010-15848 P08-FQM-03711 |
Cita | Takai, T., Higaki, K., Aguilar Moncayo, M., Mena Barragán, T., Hirano, Y., Yura, K.,...,Suzuki, Y. (2013). A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM1 Gangliosidosis. Molecular Therapy, 21 (3), 526-532. |
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