dc.creator | Castilla, Javier | es |
dc.creator | Rísquez Cuadro, Rocio | es |
dc.creator | Higaki, Katsumi | es |
dc.creator | Nanba, Eiji | es |
dc.creator | Ohno, Kousaku | es |
dc.creator | Diaz, Yolanda | es |
dc.creator | Ortiz Mellet, Carmen | es |
dc.creator | García Fernández, José Manuel | es |
dc.creator | Castillón, Sergio | es |
dc.date.accessioned | 2018-09-17T10:36:16Z | |
dc.date.available | 2018-09-17T10:36:16Z | |
dc.date.issued | 2015 | |
dc.identifier.citation | Castilla, J., Rísquez Cuadro, R., Higaki, K., Nanba, E., Ohno, K., Diaz, Y.,...,Castillón, S. (2015). Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease. European Journal of Medicinal Chemistry, 90, 258-266. | |
dc.identifier.issn | 0223-5234 (impreso) | es |
dc.identifier.issn | 1768-3254 (electrónico) | es |
dc.identifier.uri | https://hdl.handle.net/11441/78550 | |
dc.description.abstract | 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 ω-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. | es |
dc.description.sponsorship | España, Ministerio de Ciencia e Innovación DGI CTQ2011-22872-BQU, SAF2013-44021-R | es |
dc.description.sponsorship | Japan, Ministry of Education, Culture, Science, Sports and Technology 22390207 and 23591498 | es |
dc.description.sponsorship | Fondo Social Europeo (FSE) | es |
dc.description.sponsorship | Fondo Europeo de Desarrollo Regional (FEDER) | es |
dc.format | application/pdf | es |
dc.language.iso | eng | es |
dc.publisher | Elsevier | es |
dc.relation.ispartof | European Journal of Medicinal Chemistry, 90, 258-266. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Glycomimetic | es |
dc.subject | Glycosidase inhibitor | es |
dc.subject | Pharmacological chaperone | es |
dc.subject | Gaucher disease | es |
dc.subject | Glucocerebrosidase | es |
dc.subject | Lysosomal storage disorders | es |
dc.title | Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/submittedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Química Orgánica | es |
dc.relation.projectID | DGI CTQ2011-22872-BQU | es |
dc.relation.projectID | SAF2013-44021-R | es |
dc.relation.publisherversion | http://dx.doi.org/10.1016/j.ejmech.2014.11.002 | es |
dc.identifier.doi | 10.1016/j.ejmech.2014.11.002 | es |
idus.format.extent | 22 | es |
dc.journaltitle | European Journal of Medicinal Chemistry | es |
dc.publication.volumen | 90 | es |
dc.publication.initialPage | 258 | es |
dc.publication.endPage | 266 | es |