The close interaction between organic chemi stry and biology goes back to the late 18th century, when the modern natural sciences began to take shape. After synthetic organic chemistry arose as a discipline, organic chemists almost immediately began to pursue the synthesis of naturally occurring compounds,…

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

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process.

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.

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

Promotor: H.S. Overkleeft, Co-Promotor: B.I. Florea

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

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

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…

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…

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.

This thesis describes the use of an activity-based proteomics method to study the endocannabinoid system.

Lysosomal glycosidases are acid hydrolases that fragment glycoconjugates in lysosomes.

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

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

A new technique using fluorescent imaging to track the actions of enzymes might aid drug design for new anti-cancer, inflammation and kidney disease treatments. Researchers at the University of York and Leiden University have published these findings in Nature Chemical Biology.

PhD Defence

PhD Defence

Promotor: H.S. Overkleeft, Co-promotor: B.I. Florea

PhD Defence

Conference

PhD Defence

Lecture

PhD Defence

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

A model method: A strategy that combines a knowledge-based in silico design approach and the development of novel activity-based probes (ABPs) for the detection of endogenous diacylglycerol lipase-α (DAGL-α) is presented. This approach resulted in the rapid identification of new DAGL-α inhibitors with…

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

In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.

Molecular Physiology is a research group at the Leiden Institute of Chemistry, headed by Prof. Mario van der Stelt. The research aim is to design, synthesize and apply new chemical tools to answer important biological and medical questions. We use activity-based protein profiling, assay development,…

Overview of Molecular Physiology publications

Research at the BIOSYN group is comprised of the following research themes:

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

Annelot van Esbroeck-Weevers, PhD student at the Molecular Physiology research group at the Leiden Institute of Chemistry, headed by Dr. Mario van der Stelt, has been awarded the Best Oral Communication Prize at the 8th European Workshop on Cannabinoid Research, held from 31 August to 2 September 2017…

A European consortium has provided a disruptive technological breakthrough to allow the discovery and characterization of novel enzymes for industrial biotechnology. The technology will open the way to more efficient industrial processes such as in the biofuel, animal feed and paper and pulp industr…

Mario van der Stelt (Head of the department of Molecular Physiology at the Leiden Institute of Chemistry) has received the Young Investigator Award from the International Cannabinoid Research Society during the annual meeting of the society in Montreal, Canada. The Young Investigator Award was given…

With cancer, a person’s body cells grow uncontrollably. Putting together a detailed picture of how this comes about makes it possible to develop efficient therapies. Researchers at the Leiden University Medical Centre (LUMC) and Leiden University are working together to gain a better understanding…

There are many complex links in the chain that provides patients with new drugs: from fundamental science, to clinical tests, to production. The entire chain can be found in Leiden. The University, the Leiden University Medical Center (LUMC) and the businesses at the Leiden Bio Science Park (LBSP) work…

Endocannabinoids - the body's own marijuana - are promising departure points for drug research. Professor of Molecular Physiology Mario van der Stelt examines whether inhibiting their production can be a way to fight inflammatory brain disease and to combat obesity. Inaugural lecture 19 October.

At high doses, drug candidate BIA 10-2474 binds not only to the protein that it targets, but to other proteins as well. It thus deactivates proteins that are involved in the metabolism of nerve cells. This is what an international group of researchers from Leiden University and Erasmus MC, among others,…

How do you ensure that a drug has an effect on the right protein – and nothing else? Chemist Anthe Janssen explored various methods for determining the selectivity of potential medicines. He also looked at the substance BIA 10-2474, after a man died in a French clinical trial in 2016. PhD defence on…

Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion, but they are currently lacking.…

Lecture

A high-end label: Cyclophellitol aziridine-type activity-based probes allow for ultra-sensitive visualization of mammalian β-glucosidases (GBA1, GBA2, GBA3, and LPH) as well as several non-mammalian β-glucosidases (see picture). These probes offer new ways to study β-exoglucosidases, and configurational…

Lecture

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

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

Promotor: M. Ubbink, Co-promotor: G. Siegal