Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
Teresa Mena-Barragán,
M. Isabel García-Moreno,
Alen Sevšek,
Tetsuya Okazaki,
Eiji Nanba,
Katsumi Higaki,
Nathaniel I. Martin,
Roland J. Pieters,
José M. García Fernández,
Carmen Ortiz Mellet
Affiliations
Teresa Mena-Barragán
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41011 Sevilla, Spain
M. Isabel García-Moreno
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41011 Sevilla, Spain
Alen Sevšek
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
Tetsuya Okazaki
Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago 680-8550, Japan
Eiji Nanba
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan
Katsumi Higaki
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan
Nathaniel I. Martin
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
Roland J. Pieters
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
José M. García Fernández
Instituto de Investigaciones Químicas (IIQ), CSIC—University of Sevilla, Avda. Americo Vespucio 49, 41092 Sevilla, Spain
Carmen Ortiz Mellet
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41011 Sevilla, Spain
A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.
