Supervisor: Xue Yang

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

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…

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.

Many biological processes occur by biomolecules coming together and organizing into specific clusters without being bound to each other. These interactions range from clustering, transiently interacting (kiss and run), or assembling to multimeric units that can only function in conjunction. The hydrogen…

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.

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

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

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

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).

Promotores: H.S. Overkleeft; G.A. van der Marel Co-Promotor: B.I. Florea

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

Supervisor: Anna Vlachodimou

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

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

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…

This Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars.

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.

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

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

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

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

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

Due to their central physiological roles in living organisms, retaining beta-glycosidases have been the subject of tremendous research efforts to examine their structure/function relation using numerous biophysical and biochemical approaches.

Glycosidases are important enzymes in the turnover of polysaccharides and glycoconjugates, and are involved in a range of human pathologies including genetic disorders such as Gaucher and Pompe disease, but also in various cancers.

The current projects of the Molecular Physiology group focus on proteins of the endocannabinoid system, kinases and antibacterial targets. MSc- and BSc-students can contact Jessica van Krimpen-Kraaijenoord to apply for research internships.

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

Grants awarded to molecular physiology research

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.

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

Promotor: J.P. Abrahams, Co-Promotor: N.S. Pannu

PhD defence

The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered…

The discovery of new medicines is a tedious and lengthy process. On average, over 10,000 molecules need to be studied for one to become a drug and reach the patient. Part of that process are the very costly clinical trials in humans, and candidate drugs often fail due to side effects or lack of efficacy.…

Source: Br. J. Pharmacol., Volume 172, Issue 3, pp. 940-55 (2015)

Activity-based protein profiling (ABPP, also termed chemical proteomics), is one of the pillars of chemical biology, and at LED3 we have taken it to the next level. ABPP allows the assessment of protein function in live cells and tissues, which means that the activity of a complete protein family can…

The research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a dismal prognosis and limited therapeutic options.

Activity-based protein profiling (ABPP) is a functional proteomics technique for directly monitoring the expression of active enzymes in cell extracts and living cells. The technique relies on irreversible inhibitors equipped with reactive groups (warheads) that covalently attach to the active site…

To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases.

Promotores: B. van de Water; P. Hogendoorn; J. Bovée Co-Promotor: E.H.J. Danen

Vitamin A or retinol is essential in embryonic development, the visual cycle and the immune system.

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…

Thomas Bakkum en Tom van der Wel, two PhD candidates from the Leiden Institute of Chemistry, have both won poster prizes at the EMBL Chemical Biology Conference 2018 in Heidelberg.

For her bachelor’s thesis, Molecular Science and Technology student Madouc Bergers synthesized her own molecule that can inhibit the breakdown of sugars. Although most students do not even manage to make one building block, Madouc made three. Partly because of this, she has been nominated for the Science…

This thesis explores different avenues to develop insurmountable antagonists for CC Chemokine Receptors, such as CCR1, CCR2 and CCR5.