May 29, 2024
Stress Response

Scientists Develop New Agent to Selectively Inhibit Stress Response

Researchers at ETH Zurich have developed a breakthrough agent that targets and eliminates the control center of the body’s stress response, known as the glucocorticoid receptor. Chronic stress has been linked to various negative effects on the body, including obesity, cardiovascular diseases, increased susceptibility to infection, memory disorders, and depression. Current medical treatments focus on managing the symptoms of these secondary conditions, with limited success.

The only approved drug that directly affects stress response regulation is associated with unwanted side effects and was not originally developed for this purpose. However, the new agent developed by the research group at ETH Zurich shows promise in specifically addressing stress-related conditions such as chronic depression, with fewer side effects. By targeting the glucocorticoid receptor, the researchers prevent the stress hormone cortisol from triggering the stress response.

The glucocorticoid receptor plays a crucial role in activating genes responsible for the stress response. When cortisol bonds with the glucocorticoid receptor, the body experiences typical stress symptoms such as an elevated pulse rate, increased blood flow to muscles, heightened concentration, and decreased pain perception. The new agent, unlike the previously approved drug, focuses solely on the glucocorticoid receptor, minimizing the risk of unwanted side effects.

The researchers used a method called proteolysis-targeting chimera (PROTAC) to target the receptor proteins and initiate natural degradation. PROTAC drug molecules consist of two functional subunits connected to each other. One subunit binds to an enzyme that chemically tags the proteins targeted for degradation, while the other subunit selectively binds to the specific protein of interest (POI) to be deactivated. This proximity ensures that the protein is tagged and subsequently degraded.

However, achieving selective tagging of the glucocorticoid receptor proved to be challenging in the lab. The success of the method depends on precise binding between the two subunits and the tagging enzyme and receptor. The research project required collaboration across multiple disciplines, with expertise from organic chemists, measurement specialists, and neuroscience researchers.

While the study shows promising results, further research is needed to understand the molecule’s mechanisms within cells, dose-response relationships, interactions with other molecules, and absorption, dispersion, and metabolism within the body. The researchers estimate that it will be several years before applications are ready for patients.

The lead researcher, Katharina Gapp, believes that the PROTAC method has significant potential in developing new drugs. Unlike current agents that can only target one receptor each, a single PROTAC molecule can tag multiple proteins of interest in succession. This allows for lower doses and reduces the risk of side effects.

In conclusion, the development of this new agent targeting the glucocorticoid receptor could revolutionize the treatment of stress-related conditions, offering more specific and effective therapies with minimal side effects. The researchers are optimistic about the potential of the PROTAC method in creating new drugs that can address a range of medical conditions.

1. Source: Coherent Market Insights, Public sources, Desk research
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