Stress isn’t merely an oppressive feeling we experience when we’re overwhelmed; it’s the body’s natural reaction to acute or persistent strain. This stress response is what enables us to quickly adapt to danger or a shift in conditions. But if this response – which is essential for survival – gets out of control and becomes a permanent state, it can trigger a wide range of negative effects: obesity, cardiovascular diseases, increased susceptibility to infection, memory disorders and depression are all typical effects of chronic stress.
Up to now, medical treatment has focused almost entirely on the symptoms of these secondary conditions. “The only approved drug that directly intervenes in the regulation of stress responses has a host of unwanted side effects. It was actually developed as an abortifacient and its impact on stress is merely a side effect,” explains Katharina Gapp, head of the Epigenetics and Neuroendocrinology group at the Institute for Neuroscience at ETH Zurich.
In collaboration with three other ETH research groups, Gapp has now developed a promising new agent that pinpoints and eliminates the control centre of the stress response – what’s called the glucocorticoid receptor – in cell cultures and animal models. In the future, this could enable stress-related conditions such as chronic depression to be treated much more specifically and with fewer side effects.
Receptor is key to cortisol’s efficacy
By eliminating the receptor protein, the researchers are preventing the stress hormone cortisol from triggering the reaction in the first place. This is because in order to activate the genes responsible for the stress response, cortisol must bond with the glucocorticoid receptor. That’s when the body experiences the typical symptoms of stress such as elevated pulse rate, increased blood flow to muscles, a surge in metabolic activity, decreased pain perception and heightened concentration.
In contrast to the abovementioned abortifacient drug, the new ETH molecule essentially affects only the glucocorticoid receptor. This is thanks to what’s known as the proteolysis-targeting chimera (PROTAC) method, which allows the agent to target the receptor proteins and supply the cells with a natural degradation system.
The right configuration of receptor and enzyme
PROTAC drug molecules are made up of two different functional subunits that share a connection. One of the two subunits binds specifically to an enzyme, which chemically tags the proteins in the cell that are to be degraded. The second subunit is designed to bind as selectively as possible to the protein of interest (POI) targeted for deactivation. By bringing the enzyme and POI in close proximity to one another, the drug molecule ensures the protein gets tagged and thus degraded.