2024-03-28T14:41:45Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1132492022-04-19T10:55:07Zcom_10261_38com_10261_5col_10261_291
Castilla, Javier
Rísquez-Cuadro, Rocio
Higaki, Katsumi
Nanba, Eiji
Ohno, Kousaku
Díaz, Yolanda
Ortiz-Mellet, Carmen
García-Fernández, José Manuel
Castillón, Sergio
2015-04-01T10:48:58Z
2015-04-01T10:48:58Z
2015
European Journal of Medicinal Chemistry 90: 258- 266 (2015)
http://hdl.handle.net/10261/113249
10.1016/j.ejmech.2014.11.002
© 2014 Elsevier Masson SAS. 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 β-glucosidase. Notably, their inhibitory potency against human β-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 υ-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.
eng
openAccess
Glycomimetic
Glucocerebrosidase
Gaucher disease
Pharmacological chaperone
Glycosidase inhibitor
Lysosomal storage disorders
Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease
artículo