Universiteit Leiden

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Dissertation

Design and development of conformational inhibitors and activity-based probes for retaining glycosidases

Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins.

Author
Beenakker, T.J.M.
Date
19 October 2017
Links
Thesis in Leiden Repository

Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins. Malfunctioning of glycosidases causes various complex pathologies in man, for example, lysosomal storage disorders such as Fabry disease and Krabbe disease. Activity-Based Protein Profiling (ABPP) is a powerful technique to selectively analyze functional proteins in their physiological surroundings. Potent and selective activity-based glycosidase probes (ABPs) could help to understand the pathological processes connected with these enzymes. The first part of this Thesis describes the design, synthesis and application of a set of ABPs for retaining α-galactosidases, β-galactosidases, α-mannosidases and β-mannosidases.Several reversible, competitive glycosidase inhibitors have been developed in the past and are employed for therapeutic applications. The second part of this Thesis focuses on the design of functionalized bicycle [4.1.0] heptanes, carba-cyclophellitols, as new potential competitive inhibitors of glycosidases (α-galactosidases, β-galactosidases, α-glucosidases and β-glucosidases) and glycosyltransferases (both galactosyltransferases and glucosyltransferases). Herein a specific substituted carba-cyclophellitol turned out to be highly potent towards Thermotoga maritima TmGH1 β-glucosidase and therefore conformational strain induced through a cyclopropyl unit may be added to the armory of tight-binding inhibitor designs.

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