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Título: | Pharmacological Chaperones for the Treatment of α-Mannosidosis |
Autor: | Rísquez-Cuadro, Rocio; Matsumoto, R.; Ortega-Caballero, Fernando; Nanba, Eiji; Higaki, Katsumi; García Fernández, José Manuel CSIC ORCID; Ortiz Mellet, Carmen | Fecha de publicación: | 2019 | Editor: | American Chemical Society | Citación: | Journal of Medicinal Chemistry 62: 5832- 5843 (2019) | 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 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. | Versión del editor: | http://dx.doi.org/10.1021/acs.jmedchem.9b00153 | URI: | http://hdl.handle.net/10261/204099 | DOI: | 10.1021/acs.jmedchem.9b00153 | Identificadores: | doi: 10.1021/acs.jmedchem.9b00153 issn: 1520-4804 |
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J. Med. Chem. 2019, 62, 5832-5843 accepted.pdf | 1,21 MB | Adobe PDF | Visualizar/Abrir |
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