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- Title
Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease.
- Authors
Mena-Barragán, Teresa; García-Moreno, M. Isabel; Sevšek, Alen; Okazaki, Tetsuya; Nanba, Eiji; Higaki, Katsumi; Martin, Nathaniel I.; Pieters, Roland J.; Fernández, José M. García; Mellet, Carmen Ortiz
- Abstract
A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-<italic>gluco</italic> or l-<italic>ido</italic>), 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 <italic>N′</italic>-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.
- Subjects
IMINOSUGARS; GLYCOSIDASES; BICYCLIC compounds; HYDROXYLATION; MOLECULAR chaperones; GAUCHER'S disease treatment
- Publication
Molecules, 2018, Vol 23, Issue 4, p927
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules23040927