Author, as appears in the article.: Castilla J; Rísquez R; Higaki K; Nanba E; Ohno K; Suzuki Y; Díaz Y; Ortiz Mellet C; García Fernández JM; Castillón S
Department: Química Analítica i Química Orgànica
URV's Author/s: Castillón Miranda, Sergio / Díaz Giménez, María Yolanda
Keywords: Transition-state analogs Therapy Pharmacological chaperone O-glcnacase Molecular-basis Lysosomal-storage-diseases Lysosomal storage disorders Glycosidase inhibitor Glycomimetic Glucosidase inhibitors Glucocerebrosidase inhibitors Glucocerebrosidase Gaucher disease Derivatives Beta-glucosidase Alpha-galactosidase lysosomal storage disorders glycosidase inhibitor glycomimetic glucocerebrosidase gaucher disease
Abstract: © 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.
Thematic Areas: Zootecnia / recursos pesqueiros Saúde coletiva Química Pharmacology Organic chemistry Odontología Nutrição Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Interdisciplinar Farmacia Ensino Engenharias iv Engenharias ii Enfermagem Educação física Drug discovery Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Ciência da computação Chemistry, medicinal Biotecnología Biodiversidade Astronomia / física
ISSN: 02235234
Author's mail: yolanda.diaz@urv.cat sergio.castillon@urv.cat
Author identifier: 0000-0001-5567-8108 0000-0002-0690-7549
Record's date: 2024-09-07
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: European Journal Of Medicinal Chemistry. 90 258-266
APA: Castilla J; Rísquez R; Higaki K; Nanba E; Ohno K; Suzuki Y; Díaz Y; Ortiz Mellet C; García Fernández JM; 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. DOI: 10.1016/j.ejmech.2014.11.002
Article's DOI: 10.1016/j.ejmech.2014.11.002
Entity: Universitat Rovira i Virgili
Journal publication year: 2015
Publication Type: Journal Publications