Promotores: H.S. Overkleeft, G.A. van der Marel, Co-Promotor: J.D.C. Codee

This thesis describes research aimed at discovering inhibitors selective for either of the two endoplasmic reticulum α-glucosidases, ER-I and ER-II, with the overarching goal of discovering new antiviral agents to treat viruses that rely on host N-glycosylation for proliferation.

Enzymes are innately sensitive to changes in the amino acid sequence, which largely constrains their evolutionary potential, i.e., evolvability. This evolutionary burden can be alleviated in the presence of stabilizing mutations, which increase the buffering capacity of enzymes to tolerate mutations…

Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.

β-Lactamases are enzymes that can break down β-lactam substrates, such as antibiotics, preventing the use of these antibiotics for the treatment of various infectious diseases. However, some compounds, β-lactamase inhibitors, can block these enzymes allowing for possible treatments using a combination…

This thesis focuses on the design and synthesis of activity-based probes and inhibitors targeting enzymes involved in the degradation of specific plant glycans.

Glycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo/polysaccharides, glycoproteins and glycolipids with tremendous efficiency

Many metalloenzymes that are key to bioenergetics are membrane enzymes, with canonical examples the complexes I, II, III and IV in the mitochondrial inner membrane. To study these enzymes in a native-like lipid membrane environment, we aim to develop novel bioelectrochemical techniques.

Ever since the FDA approved the drug bedaquiline, which interferes with the bioenergetics of Mycobacterium tuberculosis by inhibiting the activity the F0F1-ATP synthase, respiratory-chain enzymes have been an active target space for the discovery of new antibiotics. To aid in this pursuit, we aim to…

Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central…

Pseudomonas Aeruginosa is a Gram-negative bacterium which can form biofilms, increasing its resistance against antibiotics and the host immune system. Polysaccharides are an integral part of this biofilm, one of these polysaccharides is called Psl. PslG is a glycosidase, able to cleave this polysaccharide,…

In this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the discovery of alpha-ketoamides as a hit for PLAAT3.

Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel

The spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis.

NNMT wordt beschouwd als een nieuw potentieel farmacologisch doelwit in de behandeling van een verscheidenheid van kankers, stofwisselingsziekten en andere pathologieën. Het toenemend aantal publicaties waarin de rol van NNMT bij ziekten wordt opgehelderd, heeft op zijn beurt de ontwikkeling van krachtige…

Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation.

This thesis describes the synthesis and biochemical evaluation of a variety of cyclophellitol based activity-based probes and inhibitors targeting various endo- and exo-acting retaining glycosidases. In the last two decades a variety of probes and inhibitors for (hemi)cellulose degrading enzymes have…

The primary goal of this research is to deepen our understanding of substrate-enzyme interactions in Glycoside hydrolases. For this purpose, Bacillus circulans xylanase (BcX) has been selected as a well-established model to examine the Michaelis complex and glycosyl-enzyme adduct.

Plastics are an intrinsic part of our society. Annually, 400Mt of plastics are produced of which roughly 40% is discarded within a year.

Promotor: H.S. Overkleeft, J. Neefjes, Co-promotor: M. van der Stelt

The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs).

Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.

Glycosidases (GHs) are enzymes responsible for the degradation of carbohydrates and play many roles in human health and pathophysiology. Often, abnormal levels of glycosidase activity are markedly linked to human pathologies.

The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates.

Supervisor: Anna Vlachodimou

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

The clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1…

Promotor: Prof.dr. G.P. van Wezel, Co-Promotor: E. Vijgenboom

Neuraminidases are enzymes that cleave glycosidic linkages of sialic acid. These enzymes are involved in influenza infections as well as in many cellular processes in mammals and micro-organisms.

Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…

Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…

Supervisor: Xue Yang

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Source: J Cheminform, Volume 7, Issue 1 (2015)

Can furan-based resisn be degraded by microbial enzymes in combination with mild pre-treatment?

This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes.

The thesis describes the development, synthesis and biological evaluation of several proteasome inhibitor designs. Mainly, this work focusses on designing proteasome inhibitors that selectively inhibit the immunoproteasome, while leaving the constitutive proteasome mostly, if not completely, untouch…

The chemical synthesis of inhibitors and probes targeting endo-glycosidases.

Lecture

In this thesis, a system pharmacology approach, integrating metabolomics, pharmacology and chemical biology, was applied to understand and modulate the endocannabinoid system across different model systems (cells, zebrafish, mice and humans).

How do lipases in Mycobacterium tuberculosis help the bacteria survive, and can we target them to create new antibiotics?

Learning from nature and utilizing microbial biodiversity to identify and characterize enzymes for degradation and upcycling of plastics and other polymeric materials.

Engineering an efficient microbial enzymatic polyethylene degradation pathway via an innovative combination of biochemistry and computational biology tools for enzyme discovery and characterization.

Promotor: G.P. van Wezel, Co-promotor: D. Claessen

Source: PLoS ONE, Volume 10, Issue 3 (2015)

This thesis examines enzyme domain architecture and engineering to improve the breakdown of lignocellulose and starch, abundant biopolymers crucial for sustainable biofuel and biochemical production. Carbohydrate-active enzymes (CAZymes) facilitate this degradation, but the structural complexity of…

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids.

Salicylic acid (SA) is a plant hormone, which is involved in the defense responses to pathogens and to abiotic stress, and in the regulation of plant growth and development.

This thesis explores how electron paramagnetic resonance (EPR) spectroscopy can be used to investigate key biochemical processes.

How can we develop new chemical biology tools and approaches to understand and interfere with glucosylceramide metabolism in relation to Gaucher disease?