PhD defence

Inhibitors and activity-based probes for retaining β-D-glucuronidases, heparanases and β-L-arabinofuranosidases

• V. Borlandelli

Date

Tuesday 24 October 2023

Time

13:45 - 14:30 hour

Address

Academy Building
Rapenburg 73
2311 GJ Leiden

Supervisor(s)

• Prof.dr. H.S. Overkleeft
• dr. M. Artola

Summary

Glycosidases (GHs) are enzymatic biocatalysts responsible for the degradation of carbohydrates and play many roles in human health and (patho)physiology. Often, abnormal levels of glycosidase activity are markedly linked to human pathologies. Illustrative examples of this are low levels (caused by genetic mutations) of glucocerebrosidase (GBA) in Gaucher disease and overexpression of heparanase (HPSE) in several cancer tissues. To date, the biomedical relevance of HPSE mostly pertains cancer treatment. This dissertation reports on the design, synthesis and biochemical evaluation of covalent mechanism-based inhibitors for heparanase, as well as the development of broad-spectrum activity-based probes (ABPs) for retaining exo- and endo-β-D-glucuronidases alike, including HPSE. The design of the novel inhibitors is supported by computational simulations, and the inhibition and selectivity of the newly synthesised compounds towards HPSE is demonstrated in vitro with the use of the newly developed ABPs. The thesis further builds on the concept of ABP-based profiling of GHs and discusses the development of inhibitors and probes targeting retaining β-L-arabinofuranosidases, a group of non-canonical glycosidases predominantly expressed by microorganisms of the human gut microbiome. As retaining β-L-arabinofuranosidases possess a contentious enzymatic mechanism, the novel chemical tools developed and presented in this thesis were decisive for unraveling β-L-arabinofuranosidases’ mechanism of action, and might serve in the future as probing tools for studies of the human gut microbiome.

PhD dissertations

Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.

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