Stress is not just an oppressive feeling encountered when one is overburdened; rather, it constitutes the body’s inherent response to acute or persistent strain. The stress response is responsible for facilitating prompt adaptation to peril or changes in circumstances.
However, should this physiological reaction — vital for survival — escalate and persist indefinitely, it can instigate an extensive array of adverse consequences: chronic stress is known to give rise to obesity, cardiovascular ailments, heightened vulnerability to infections, memory impairments, and depression, among other common side effects.
Until now, medical treatment has centered 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,”
said Katharina Gapp, head of the epigenetics and neuroendocrinology group at the Institute for Neuroscience at ETH Zurich.
Glucocorticoid Receptor Activation
Gapp, in collaboration with three other research groups, has developed a promising new agent that pinpoints and eliminates the stress response’s control center, known as the glucocorticoid receptor, in cell cultures and animal models. In the future, this could allow stress-related conditions to be treated more precisely and with fewer side effects.
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 is when the body exhibits typical stress symptoms such as an elevated pulse rate, increased blood flow to muscles, an increase in metabolic activity, decreased pain perception, and improved concentration.
Proteolysis-targeting Chimera Method
The new molecule, as opposed to the abortifacient drug mentioned earlier, primarily targets the glucocorticoid receptor. This is possible due to the proteolysis-targeting chimera (PROTAC) technique, which enables the agent to deliver a natural degradation system to the cells by targeting the receptor proteins.
Two functional subunits comprise PROTAC drug molecules, which are interconnected in one way or another. An enzyme is able to chemically label the proteins within the cell that are to be degraded in response to one of the two subunits binding to it.
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.
Despite the method’s apparent elegance in theory, its practical implementation proves to be exceedingly challenging.
To achieve selective tagging of the glucocorticoid receptor, it is critical that the two functional subunits bind to the tagging enzyme and the receptor in a highly specific manner. Additionally, for a particular enzyme-protein coupling, the length and nature of the connection between the two subunits must be precisely matched.
Specialized Know-how
Designing, synthesizing, and fully testing potential PROTAC agents calls for specialized know-how from a wide variety of disciplines. Gapp was able to count on the expertise of three ETH research groups: Erick Carreira’s team of organic chemists designed and synthesized the molecule variants, Andreas Hierlemann’s group at the Bio Engineering Laboratory carried out measurements in cell systems, and members of the Molecular and Behavioral Neuroscience group led by Johannes Bohacek helped test the effects in mice.
Scientists must now comprehend the precise mechanisms by which the molecule functions within cells, establishes dose-effect relationships, interacts with other molecules, and is absorbed, dispersed, and metabolized by the body in order to make progress toward the development of a drug. Several years will pass, even if everything goes to plan, before the initial applications for patients are complete.
Gapp is convinced that the PROTAC method holds vast potential for creating new drugs:
“Unlike existing agents, which are capable of blocking only one receptor each, a single PROTAC molecule is able to tag a great many POIs, one after the other.”
As a result, the required doses — and thus the number of possible side effects — are low.
Abstract
Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.
Reference:
- Gazorpak, M., Hugentobler, K.M., Paul, D. et al. Harnessing PROTAC technology to combat stress hormone receptor activation. Nat Commun 14, 8177 (2023). Doi: 10.1038/s41467-023-44031-2