Groundbreaking Agent Targets Stress at its Core: Potential Breakthrough in Chronic Stress Treatment
Stress Treatment: Stress is not just a burdensome feeling associated with being overwhelmed; it represents the body’s natural response to acute or prolonged strain. This stress reaction plays a vital role in enabling quick adaptations to danger or changing conditions. However, when this essential survival response becomes uncontrollable and lingers as a permanent state, it can unleash a spectrum of detrimental effects. Chronic stress is linked to conditions such as obesity, cardiovascular diseases, heightened vulnerability to infections, memory disorders, and depression. The wide-ranging consequences of prolonged stress emphasize the crucial need to maintain a balanced stress response for overall well-being.
Historically, medical treatments have predominantly addressed the symptoms of secondary conditions associated with chronic stress. Katharina Gapp, head of the Epigenetics and Neuroendocrinology group at the Institute for Neuroscience at ETH Zurich, underscores the limitations of the sole approved drug designed to regulate stress responses. Originally formulated as an abortifacient, this drug carries undesired side effects unrelated to stress regulation.
In collaboration with three other ETH research groups, Gapp has spearheaded the development of a promising new agent aimed at precisely targeting and eliminating the control center of the stress response—the glucocorticoid receptor—in both cell cultures and animal models. This groundbreaking advancement has the potential to pave the way for more specific and less side-effect-prone treatments for stress-related conditions, such as chronic depression. Published in Nature Communications, the study introduces the proteolysis-targeting chimera (PROTAC) method, allowing for the precise targeting of the glucocorticoid receptor for natural degradation. This innovative approach stands in contrast to existing drugs and holds significant promise for advancing treatments for stress-related disorders.
Crafting and assessing potential PROTAC agents demands a diverse skill set spanning organic chemistry, bioengineering, and molecular neurosciences. Spearheading the initiative at ETH Zurich, Katharina Gapp leveraged the expertise of three specialized research groups within the institution. The team led by Erick Carreira, experts in organic chemistry, undertook the design and synthesis of molecular variants. Measurements in cell systems were conducted by Andreas Hierlemann’s Bio Engineering Laboratory. Meanwhile, the effects were tested in mice with the assistance of Johannes Bohacek’s Molecular and Behavioral Neuroscience group. Gapp underscores the project’s evolving complexity and stresses the critical role of collaborative efforts across disciplines. ETH Zurich’s supportive environment emerges as instrumental in the success of these interdisciplinary endeavors.
The Next Phase in Drug Development for Stress Treatment
A comprehensive understanding of the molecule’s cellular operations, its dose/effect relationships, interactions with other molecules, and absorption, dispersion, and metabolism within the body. Despite favorable progress, it is anticipated to be several years before the first applications of the new drug are ready for patients. Katharina Gapp expresses confidence in the PROTAC method, highlighting its potential for creating innovative drugs. Unlike existing agents that block only one receptor each, a single PROTAC molecule can tag numerous proteins of interest (POIs) sequentially. This characteristic not only reduces required doses but also minimizes potential side effects, showcasing the vast therapeutic potential of this novel approach.
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