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Irritable bowel syndrome, chronic itching, asthma, and migraines are notorious for being challenging to treat and often stem from an overactive immune response, which can, in severe instances, be life-threatening. A research team from the University of Bonn has made a significant breakthrough by identifying a potent bioactive compound that may mitigate these symptoms and potentially lower the risk of fatal outcomes. This compound functions by obstructing a receptor found on specific immune defense cells, thereby averting a misguided immune reaction. The findings of this study have been published in Signal Transduction and Targeted Therapy.
The annoyance of a mosquito bite is a familiar experience, primarily caused by mast cells—immune cells that reside in the skin and mucous membranes and are laden with inflammatory mediators. When bitten, antibodies engage with components of the mosquito’s saliva, and this interaction can activate mast cells, resulting in the release of their inflammatory substances. This process typically leads to sensations of redness, swelling, and itching, which tend to resolve quickly or can be alleviated with appropriate ointments.
Interestingly, mast cells can also be activated without the involvement of antibodies, directly through contact with certain substances. “This can lead to allergic reactions,” explains Professor Christa Müller from the University of Bonn, noting that these specific reactions have proven difficult to manage. The underlying mechanisms of this activation remained elusive until approximately 15 years ago, when Professor Müller and her team identified a little-known receptor located in the membranes of mast cells. This receptor, when engaged by various molecular signals, prompts the release of inflammatory mediators.
Receptor triggers severe inflammatory reaction
The receptor, designated MRGPRX2, acts akin to a switch that concludes with severe, localized inflammation upon activation. “To mitigate this reaction, we need to find a way to block this switch,” states Professor Müller. Her department boasts a library of around 40,000 compounds, some of which had previously shown promise by binding to similar receptors. Ghazl Al Hamwi, a doctoral student and the first author of the study, elaborates, “We utilized cells that fluoresce when MRGPRX2 is activated, enabling us to test the efficacy of our compounds in hindering this receptor activation, thereby interrupting the fluorescent signal.”
The research team successfully identified a molecule capable of binding to MRGPRX2, effectively inhibiting it. They subsequently chemically refined this compound to create a derivative effective at remarkably low concentrations. “Collaboration with colleagues in Poland allowed us to demonstrate that this compound completely eliminated life-threatening allergic reactions in mice,” Al Hamwi notes. Following these developments, researchers at Charité Hospital in Berlin undertook a complex process to isolate and purify human mast cells, allowing for the demonstration that the identified molecule successfully binds to native MRGPRX2 on these cells, preventing the release of inflammatory agents.
Further optimization of the receptor blocker
The substance has since undergone additional optimization, enhancing its therapeutic efficacy and prolonging its action to improve its viability as a medication, rather than being rapidly metabolized by the body. The research team has also confirmed that this molecule selectively blocks the MRGPRX2 receptor, thereby minimizing the potential for unwanted side effects. “We view this as an exceptionally promising therapeutic candidate,” emphasizes Professor Müller, who is involved in the University of Bonn’s Transdisciplinary Research Areas (TRAs) focused on Life & Health, as well as Matter. However, further animal and human clinical trials are essential to ascertain the compound’s eligibility for drug approval.
If successful, this advancement could be a significant boon for patients suffering from inflammatory disorders impacting the gastrointestinal tract, respiratory system, or nervous system, as well as individuals grappling with severe chronic itching and other inflammatory skin conditions. Many such ailments not only invoke considerable pain but also correlate with reduced life expectancy. Moreover, blocking the MRGPRX2 receptor could play a crucial role in preventing anaphylactic shock, which are potentially fatal allergic reactions that may occur following specific medications.
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