Abstract
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.
Highlights
Structural analogues of carbohydrates, generically termed glycomimetics, with the ability to interfere with sugar-processing enzymes have proven extremely useful for the investigation of mechanistic aspects pertaining to enzymatic glycoside hydrolysisMolecules 2018, 23, 927; doi:10.3390/molecules23040927 www.mdpi.com/journal/moleculesMolecules 2018, 23, 927 or formation and the biochemical routes in which oligosaccharides and/or glycoconjugates are involved
Mutations in the gene encoding for acid α-galactosidase leads to a misfolded mutant protein, ensuing endoplasmic reticulum associated degradation (ERAD), and the accumulation of its putative substrate in the lysosomes
The excess of substrate displaces the glycomimetic and the hydrolytic activity is restored, a rescuing mechanism known as pharmacological chaperone therapy [12,13,14,15]
Summary
Structural analogues of carbohydrates, generically termed glycomimetics, with the ability to interfere with sugar-processing enzymes (glycosidases, glycosyltransferases) have proven extremely useful for the investigation of mechanistic aspects pertaining to enzymatic glycoside hydrolysis. Α-reducing derivatives such as 1 and 2 (Figure 1) were found to behave as very selective inhibitors of the commercial β-glucosidases from almonds, bovine liver, and Thermotoga maritima in a preliminary screening against a panel of commercial glycosidases, and as very efficient chaperones for a series of mutant GCase forms associated to Gaucher disease [23,73,74]. All these β-glucosidases belong to the glycosyl hydrolase family GH1 in the CAZy classification [75], meaning that they share considerable analogy in their active site architecture. C-5 in monosaccharides (DNJ or DIJ derivatives; 4–6 and 10–12 vs. 7–9 and 13–15), and (d) the nature of nonglycone-type substituents in the inhibitory/chaperoning properties (octyl, butyl, or phenyl)
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