Stress, a natural response to challenging situations, can be more than just a fleeting emotion—it poses a significant impact on our overall health. The body’s stress response, designed to help us adapt swiftly to danger, can become problematic when it lingers, leading to various health issues such as obesity, heart disease, increased infection risk, memory problems, and depression.
Traditional medical treatments have often focused on alleviating the symptoms of stress-related conditions. However, a recent breakthrough may change the landscape of stress management. Katharina Gapp, from the Institute for Neuroscience at ETH Zurich, alongside three other research groups, has developed a novel agent that targets the stress control center—the glucocorticoid receptor.
The glucocorticoid receptor plays a crucial role in the stress response. When the stress hormone cortisol binds to this receptor, it activates genes responsible for the stress response, leading to physiological changes like a faster pulse, increased blood flow to muscles, higher metabolic activity, reduced pain perception, and improved concentration. The challenge lies in regulating this process without unwanted side effects.
Unlike existing drugs, the new agent developed by Gapp and her collaborators specifically targets the glucocorticoid receptor. This is achieved through the Proteolysis-Targeting Chimera (PROTAC) method, a revolutionary approach in drug development. The ETH molecule aims to eliminate the receptor protein, preventing cortisol from causing a stress reaction.
The PROTAC method involves a drug composed of two connected parts. One part attaches to an enzyme, marking proteins in the cell for degradation, while the other part binds to the targeted protein of interest (POI) to deactivate it. In this case, the drug binds the enzyme and the glucocorticoid receptor, ensuring the receptor protein is tagged and degraded.
Implementing the PROTAC method in the laboratory, however, is no small feat. Precise binding of the two parts to the tagging enzyme and the receptor requires meticulous attention to detail. The length and type of connection must align perfectly with the specific enzyme-protein pairing.
Collaboration across diverse disciplines was crucial for the success of this project. Gapp worked with experts in organic chemistry, bioengineering, and molecular neurosciences. Erick Carreira’s organic chemistry team designed molecule variants, Andreas Hierlemann’s Bio Engineering Laboratory conducted measurements in cell systems, and Johannes Bohacek’s Molecular and Behavioral Neuroscience group tested the effects in mice.
While the process is complex, Gapp is optimistic about the potential of the PROTAC method in creating new drugs. Unlike current agents that can block only one receptor, a single PROTAC molecule can tag numerous proteins of interest sequentially. This breakthrough offers the promise of lower doses and potentially fewer side effects.
Despite the optimism, developing a drug involves understanding its functions in cells, dosage effects, interactions with other molecules, and how the body absorbs, disperses, and metabolizes it. Even with smooth progress, it will take several years before the first applications are ready for patients.
In conclusion, the PROTAC method presents significant potential for the development of new drugs that can precisely target and modulate the stress response. This groundbreaking study opens doors to more effective and targeted treatments for stress-related conditions such as chronic depression. The ability of the PROTAC method to tag multiple proteins with a single molecule holds the key to minimizing side effects and enhancing the precision of stress-related disorder treatments.
References:
- Institute for Neuroscience at ETH Zurich
- Carreira E, et al. (Year). Title of the Organic Chemistry Study. Journal Name, Volume(Issue), Page Range.
- Hierlemann A, et al. (Year). Title of the Bio Engineering Study. Journal Name, Volume(Issue), Page Range.
- Bohacek J, et al. (Year). Title of the Molecular and Behavioral Neuroscience Study. Journal Name, Volume(Issue), Page Range.
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