University of Bonn-guided study leads to the discovery of a promising receptor blocker

Irritable bowel syndrome, chronic itching, asthma and migraine are in many cases hard-to-treat conditions. They have in common that they are triggered by an excessive immune response—which in severe cases can be life-threatening. A team of researchers led by the University of Bonn has now identified a promising bioactive compound that could effectively reduce symptoms and slash fatality risk. The compound blocks a receptor on certain defense cells, thus preventing a derailed immune response. The study findings have been published in the journal Signal Transduction and Targeted Therapy.

If you have ever been bitten by a mosquito, you will know how annoying the resulting itching can be. This is in large part due to mast cells—immune cells found in the skin and mucous membranes that are full of inflammatory messengers. When a person is bitten, antibodies bind to substances in the mosquito’s saliva, and this complex can activate the mast cells, which then release their payload all at once. This leads to the symptoms of redness, swelling and itching, which usually subside after a short while, or even quicker using the right ointment.

Mast cells however can also be activated through direct contact with a substance, i.e. without antibodies being involved in the process. “This triggers allergic reactions,” explains Professor Christa Müller of the University of Bonn,“ of a specific nature that have been difficult to treat, and remain so to this day.” It was unknown by what mechanism the activation process takes place until about 15 years ago. Professor Müller (Head of Pharmaceutical and Medicinal Chemistry) and her research group became aware of a receptor in the membrane surrounding mast cells which was barely known.
When various molecular signals dock onto this receptor, inflammatory messenger substances are released.

Receptor triggers severe inflammatory reaction

A receptor with the cryptic name of MRGPRX2 acts like a kind of switch, causing severe local inflammation when activated. “To prevent this reaction, the switch would have to be blocked somehow,” says Professor Müller, “The question was: how?” Her department has a collection of roughly 40,000 compounds, including several that in trials have already been seen binding to related receptors. The study’s first author Ghazl Al Hamwi, a doctoral student of Professor Müller, explains, “We used cells that light up when
MRGPRX2 is activated, so we could then test whether the substances effectively block activation of the receptor, switching off the light signal.”

The researchers discovered that one active molecule can dock onto the receptor and block it. They then chemically modified that substance to make a derivative that is still effective even in extremely low concentrations.
“In collaboration with colleagues from Poland we were able to demonstrate that this process eliminated life-threatening allergic reactions in mice entirely,” Al Hamwi relates. Drawing upon these findings, researchers at Charité hospital in Berlin isolated and purified human mast cells through a highly complex process. The research groups involved were then able to demonstrate that the discovered molecule also docks onto native MRGPRX2 expressed on those cells to prevent the release of inflammatory messenger substances.

Further optimization of the receptor blocker

Researchers have since further optimized the substance, making it even more effective while also increasing its duration of effect for suitability as a medicinal drug, rather than being swiftly broken down by the body. The researchers involved were furthermore able to show that the molecule exclusively blocks the MRGPRX2 receptor, reducing risk from unwanted side effects. “We thus see this as an extremely promising substance,” emphasizes Professor Müller , who is also a member of the University of Bonn Transdisciplinary Research Areas (TRAs) Life & Health and Matter. Further animal and human trials are necessary to establish whether the active substance can actually be approved as a drug.

It will be good news if it can. Patients with inflammatory conditions of the gastrointestinal tract, lungs or nervous system and sufferers of severe chronic itching and other inflammatory skin diseases could benefit substantially. Not only are many of these diseases very painful, they are also associated with shortened life expectancy. Blocking the MRGPRX2 receptor could also prevent cases of anaphylactic shock—potentially fatal allergic reactions—from occurring following the administration of certain medications.

Institutions involved and funding secured:

The University of Bonn, KU Leuven (Belgium), the University of Pennsylvania (US), Charité Berlin, Ruhr University Bochum, Jagiellonian University of Krakow (Poland) and Erlangen University Hospital participated in the study.
The study was funded by the German Federal Ministry of Education and Research (BMBF) and the US National Institutes of Health (NIH).