title: Conformationally-locked N-glycosides: exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease.
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.
authors.affiliation: Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Castilla
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Profesor García González 1, 41012 Sevilla, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Rísquez
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Sanin Rosai Hospital, Yonago 683-8605, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo 204-8588, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona, Spain. Electronic address: yolanda.diaz@urv.cat.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Díaz
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Profesor García González 1, 41012 Sevilla, Spain. Electronic address: mellet@us.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, C/ Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.affiliation: Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Castillón
mesh_terms: D002236:Carbohydrate Conformation; D015195:Drug Design; D005776:Gaucher Disease / Q000188:drug therapy*; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005960:Glucosides; D018832:Molecular Chaperones; D010080:Oxazoles; D005962:Glucosylceramidase
keywords: Gaucher disease; Glucocerebrosidase; Glycomimetic; Glycosidase inhibitor; Lysosomal storage disorders; Pharmacological chaperone