Artículo
Pharmacological Chaperones for the Treatment of α-Mannosidosis
Autor/es | Rísquez Cuadro, Rocío
Matsumoto, Reimi Ortega Caballero, Fernando Nanba, Eiji Higaki, Katsumi García Fernández, José Manuel Ortiz Mellet, Carmen |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2019 |
Fecha de depósito | 2022-12-13 |
Publicado en |
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Resumen | α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme ... α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5N,6O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation. |
Agencias financiadoras | Ministerio de Economía y Competitividad (MINECO). España Junta de Andalucía Japan Society for the Promotion of Science |
Identificador del proyecto | SAF2016-76083-R
CTQ2015-64425-C2-1-R FQM2012-1467 17K10051 |
Cita | Rísquez Cuadro, R., Matsumoto, R., Ortega Caballero, F., Nanba, E., Higaki, K., García Fernández, J.M. y Ortiz Mellet, C. (2019). Pharmacological Chaperones for the Treatment of α-Mannosidosis. Journal of Medicinal Chemistry, 62 (12), 5832-5843. https://doi.org/10.1021/acs.jmedchem.9b00153. |
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Pharmacological Chaperones.pdf | 1.178Mb | [PDF] | Ver/ | |