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Stress isn't just a bad feeling you get when you feel overwhelmed. It is the body's natural reaction to difficult situations. This stress response helps us quickly adapt to danger and change. However, when this response becomes constant, it can lead to a variety of health problems, including obesity, heart disease, increased risk of infection, memory problems, and depression.

Traditional medicine has primarily addressed the symptoms of these problems. The only approved drug for stress regulation has undesirable side effects and was originally developed for a different purpose. Katharina Gapp from the Institute of Neuroscience at ETH Zurich explains this challenge.

Gapp collaborated with three other ETH research groups to create a new drug that targets stress control centers known as glucocorticoid receptors in cells and animals. This breakthrough could lead to more accurate and fewer side-effect treatments for stress-related diseases such as chronic depression.

Researchers are trying to block the stress hormone cortisol from triggering a response by removing the receptor protein. Cortisol must bind to glucocorticoid receptors to activate the genes responsible for the stress response. This is when typical stress symptoms occur, such as increased pulse rate, increased blood flow to muscles, increased metabolic activity, decreased pain perception, and improved concentration.

Unlike abortion pills, the new ETH molecule only affects glucocorticoid receptors. This is made possible by the proteolytic targeting chimera (PROTAC) method, which allows drugs to target receptor proteins and provide cells with a natural degradation system.

The PROTAC drug consists of two connected parts. Some bind to enzymes and mark proteins in cells for degradation. The other part binds to the targeted protein of interest (POI) and inactivates it. This drug binds to the enzyme and her POI, ensuring that the protein is tagged and degraded.

Although this method is elegant in theory, it is difficult to implement it in the laboratory. Successful glucocorticoid receptor tagging requires precise binding of the two moieties to the tagging enzyme and receptor. The length and type of connection must be precisely matched to the specific enzyme and protein combination.

Creating and testing potential PROTAC drugs requires expertise in organic chemistry, bioengineering, and molecular neuroscience. Gapp collaborated with three ETH research groups. Erik Carreira's organic chemistry team designs and synthesizes molecular variants, Andreas Hjermann's bioengineering laboratory performs measurements in cell systems, and Johannes Bohacek's molecular behavioral neuroscience group We tested the effect on mice. Gap recalls: “As the project progressed, it became larger and more complex.  Collaboration with leading experts from such a variety of fields was essential to its success. ``To develop a drug, scientists need to understand how the molecule functions within cells, the effects of its administration, its interactions with other molecules, and how the body works.'' We need to understand how it is absorbed, distributed, and metabolized. Even if all goes well , it will be several years before the first applications are available to patients. Gapp believes that the PROTAC method has great potential to generate new medicines. current drugs that can only block one receptor, a single PROTAC molecule can tag numerous proteins of interest one after the other. 

This means lower doses and potentially fewer side effects. This groundbreaking research opens new possibilities for the development of drugs that can specifically target and modulate the stress response, making them more effective and targeted against stress-related diseases such as chronic depression. possible to provide a cure. The ability of the PROTAC method to tag multiple target proteins with a single molecule is expected to minimize side effects and increase the accuracy of stress-related disorder treatments.