Autor según el artículo: Castillón, S. García Fernández, J.M. Ortiz Mellet, C. Díaz, Y. Suzuki, Y. Ohno, K. Nanba, E. Higaki, K. Rísquez, R. Castilla, J.

Departamento: Enginyeria Química

Resumen: Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian ß-glucosidase. Notably, their inhibitory potency against human ß-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of ?-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity.

Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 0223-5234

Página final: 266

Volumen de revista: 90

Versión del articulo depositado: info:eu-repo/semantics/submittedVersion

Enlace a la fuente original: http://www.sciencedirect.com/science/article/pii/S0223523414010241

DOI del artículo: 10.1016/j.ejmech.2014.11.002

Entidad: Universitat Rovira i Virgili.

Año de publicación de la revista: 2015

Página inicial: 258