Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

Molecules

Tetsuya Okazaki¹  JoséM. García Fernández¹  CarmenOrtiz Mellet²  RolandJ. Pieters²  Alen Sevšek²  Teresa Mena-Barragán³  M.Isabel García-Moreno³  Eiji Nanba⁴  NathanielI. Martin⁵  Katsumi Higaki⁵ 

[1] Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands;;Department of Chemical Biology &Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41011 Sevilla, Spain;Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago 680-8550, Japan;Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan;

关键词: sp2-Iminosugars;    deoxynojirimycin;    glycosidase inhibitors;    glucocerebrosidase;    chaperones;    Gaucher disease;   

DOI  :  10.3390/molecules23040927

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown