Dissertation

Chemical biology studies on retaining exo-β-glucosidases

The research described in this thesis centered on retaining exo-β-glucosidases implicated in health and disease, in particular the human inherited lysosomal storage disorder, Gaucher disease (GD).

Author: Q. Su
Date: 06 November 2024
Links: Thesis in Leiden Repository

There are three cellular retaining exo-β-glucosidases in humans: acid lysosomal β-glucosidase (GBA1), non-lysosomal β-glucosidase (GBA2), and cytosolic broad-specificity β-glucosidase (GBA3). Activity-based probes (ABPs) based on cyclophellitol or cyclophellitol aziridine scaffold have been reported as powerful tools for detecting retaining exo-β-glucosidases in cells and tissue extracts, as well as in intact cells. Broad-spectrum covalent ABPs able to label all human retaining exo-β-glucosidases, as well as GBA1-selective covalent inhibitors and ABPs, have been developed prior to this thesis. However, selective covalent inhibitors and ABPs for GBA2 or GBA3 are currently lacking. This thesis describes the exploration of new covalent inhibitors and ABPs targeting retaining exo-β-glucosidases. The β-D-xylose-configured cyclophellitol was found to be a GBA1-selective inhibitor. Unprecedented GBA2-selective covalent ABPs based on β-D-arabinofuranose-configured cyclophellitol aziridine were also discovered. Some relatively GBA3-selective ABPs were found as well. In addition, by applying established retaining exo-β-glucosidase inhibitors and ABPs, potential β-glucosidases in Caenorhabditis elegans and Nicotiana tabacum were also investigated.