Conformationally-locked N-glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease

•Glucopyranose–2-alkylsulfanyl-1,3-oxazolines are selective inhibitors of β-glucosidase.•Binding to human β-glucocerebrosidase strongly depends on aglycone-type interactions.•Structure–activity relationship studies point to long-range favorable contacts.•Incorporation of H-bond acceptor groups in an S-hexadecyl chain was found favorable.•New pharmacological chaperones for Gaucher disease have been identified.

Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose–2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian β-glucosidase. Notably, their inhibitory potency against human β-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of ω-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity.

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