Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
by
Teresa Mena-Barragán 1, M. Isabel García-Moreno 1, Alen Sevšek 2, Tetsuya Okazaki 3, Eiji Nanba 4, Katsumi Higaki 4,*, Nathaniel I. Martin 2,*, Roland J. Pieters 2,*
, José M. García Fernández 5,* and Carmen Ortiz Mellet 1,*
, José M. García Fernández 5,* and Carmen Ortiz Mellet 1,*
1
Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/Profesor García González 1, 41011 Sevilla, Spain
2
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
3
Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago 680-8550, Japan
4
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan
5
Instituto de Investigaciones Químicas (IIQ), CSIC—University of Sevilla, Avda. Americo Vespucio 49, 41092 Sevilla, Spain
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(4), 927; https://doi.org/10.3390/molecules23040927
Received: 26 March 2018 / Revised: 26 March 2018 / Accepted: 12 April 2018 / Published: 17 April 2018
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
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.
View Full-Text
Keywords:
sp2-Iminosugars; deoxynojirimycin; glycosidase inhibitors; glucocerebrosidase; chaperones; Gaucher disease
▼
Show Figures
Graphical abstract
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Mena-Barragán, T.; García-Moreno, M.I.; Sevšek, A.; Okazaki, T.; Nanba, E.; Higaki, K.; Martin, N.I.; Pieters, R.J.; Fernández, J.M.G.; Mellet, C.O. Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease. Molecules 2018, 23, 927.
Show more citation formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.
- Supplementary File 1:
PDF-Document (PDF, 1180 KB)
