Cyclophellitol is a naturally occurring cyclitol epoxide emulating the stereochemistry of beta-D-glucopyranose. It adopts a half-chair conformation and thereby mimics the transition state that emerges during hydrolysis of beta-glucosidic linkages as catalyzed by retaining beta-glucosidases. As a consequence, cyclophellitol fits very well in the enzyme active site and presents an electrophile that reacts with the catalytic nucleophile to form a covalent and irreversible bond. In this lecture, I will demonstrate how these properties can be exploited to develop activity-based retaining beta-glucosidase probes, and how, by altering stereochemistry and substitution pattern, cyclophellitol-based probes can be derived that target a variety of retaining exo- and endoglycosidases. I will focus on the design and synthesis of cyclophellitol-based glycosidase inhibitors and probes, including our recent results in the glycosylation of cyclophellitol precursors. As well, I will present examples on the application of the activity-based glycosidase probes in biomedicine (diagnostics, competitive inhibitor discovery) and biotechnology (characterization of endoglycosidases for biomass degradation).

Covalent glycosidase inhibitors in glycobiology research: Activity-based profiling of exo- and endoglycosidases

2019 Fall National Meeting

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