Articles producció científica> Química Analítica i Química Orgànica

Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease

  • Dades identificatives

    Identificador: imarina:5632196
    Autors:
    Castilla JRísquez RHigaki KNanba EOhno KSuzuki YDíaz YOrtiz Mellet CGarcía Fernández JMCastillón S
    Resum:
    © 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.
  • Altres:

    Autor segons l'article: Castilla J; Rísquez R; Higaki K; Nanba E; Ohno K; Suzuki Y; Díaz Y; Ortiz Mellet C; García Fernández JM; Castillón S
    Departament: Química Analítica i Química Orgànica
    Autor/s de la URV: Castillón Miranda, Sergio / Díaz Giménez, María Yolanda
    Paraules clau: 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
    Resum: © 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.
    Àrees temàtiques: 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
    Adreça de correu electrònic de l'autor: yolanda.diaz@urv.cat sergio.castillon@urv.cat
    Identificador de l'autor: 0000-0001-5567-8108 0000-0002-0690-7549
    Data d'alta del registre: 2024-09-07
    URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
    Referència a l'article segons font original: European Journal Of Medicinal Chemistry. 90 258-266
    Referència de l'ítem segons les normes 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
    DOI de l'article: 10.1016/j.ejmech.2014.11.002
    Entitat: Universitat Rovira i Virgili
    Any de publicació de la revista: 2015
    Tipus de publicació: Journal Publications
  • Paraules clau:

    Chemistry, Medicinal,Drug Discovery,Medicine (Miscellaneous),Organic Chemistry,Pharmacology
    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
    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
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