New agent halts stress response

PROTAC tech targets stress receptors.

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Stress isn’t just a harsh feeling when overwhelmed; it’s the body’s natural reaction to challenging situations. This stress response helps us adapt quickly to danger or changes. However, if this response becomes constant, it can cause various health issues like obesity, heart disease, increased infection risk, memory problems, and depression.

So far, medical treatment has mainly dealt with the symptoms of these issues. The only approved drug for stress regulation has unwanted side effects and was initially developed for another purpose. Katharina Gapp from the Institute for Neuroscience at ETH Zurich explains this challenge.

With three other ETH research groups, Gapp has created a new agent targeting the stress control center, known as the glucocorticoid receptor, in cells and animals. This breakthrough could lead to more precise and fewer side-effect treatments for stress-related conditions like chronic depression.

The researchers are stopping the stress hormone cortisol from causing a reaction by eliminating the receptor protein. Cortisol needs to bind with the glucocorticoid receptor to activate the genes responsible for the stress response. This is when typical stress symptoms occur, like a faster pulse, increased blood flow to muscles, higher metabolic activity, reduced pain perception, and improved concentration.

Unlike the abortifacient drug, the new ETH molecule only affects the glucocorticoid receptor. This is possible through the proteolysis-targeting chimera (PROTAC) method, allowing the agent to target the receptor proteins and provide cells with a natural degradation system.

A PROTAC drug consists of two parts that are connected. One part attaches to an enzyme, marking the proteins in the cell for degradation. The other part binds to the targeted protein of interest (POI) to deactivate it. This drug binds the enzyme and POI, ensuring the protein is tagged and degraded.

Although the method is elegant in theory, achieving it in the lab is challenging. Successful tagging of the glucocorticoid receptor requires precise binding of the two parts to the tagging enzyme and the receptor. The connection’s length and type must exactly match the specific enzyme-protein pairing.

Creating and testing potential PROTAC agents involves organic chemistry, bioengineering, and molecular neurosciences expertise. Gapp collaborated with three ETH research groups: Erick Carreira’s organic chemistry team designed and synthesized 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.

Gapp recalls, “As the project went on, it became more extensive and complex. “The collaboration with leading specialists from such varied disciplines was essential for success. ETH provides the ideal framework for this kind of endeavor.”

To develop a drug, scientists must understand how the molecule functions in cells, its dosage effects, interactions with other molecules, and how the body absorbs, disperses, and metabolizes it. Even if everything progresses smoothly, it will take several years before the first applications are ready for patients.

Gapp believes the PROTAC method has significant potential for creating new drugs. Unlike current agents that can block only 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 study opens new possibilities for developing drugs that can specifically target and modulate the stress response, potentially offering more effective and targeted treatments for stress-related conditions such as chronic depression. The PROTAC method’s ability to tag multiple proteins of interest with a single molecule holds promise for minimizing side effects and enhancing the precision of stress-related disorder treatments.

Journal reference:

  1. Gazorpak, M., Hugentobler, K.M., Paul, D. et al. Harnessing PROTAC technology to combat stress hormone receptor activation. Nature Communications. DOI: 10.1038/s41467-023-44031-2.

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