MINNEAPOLIS/ST. PAUL — In a groundbreaking discovery, researchers at the University of Minnesota Medical School have unveiled a novel method to rewire G protein-coupled receptor (GPCR) signaling, potentially revolutionizing the way medicines are developed. The study, published today in Nature, introduces “molecular bumpers” and “molecular glues” that transform these cell receptors into precision tools, paving the way for a new generation of safer, more effective drugs.
GPCRs are a significant focus in pharmacology, with about one-third of all FDA-approved drugs targeting this receptor family. Despite their success, the potential of GPCRs remains largely untapped, as they can activate multiple signaling pathways that lead to varied physiological effects. While some of these effects are beneficial, others can cause undesirable side effects, posing challenges in drug development.
“The capability to design drugs that produce only selected signaling outcomes may yield safer, more effective medicines. Until now, it hasn’t been obvious how to do this,” said Lauren Slosky, PhD, an assistant professor at the University of Minnesota Medical School, and the senior and corresponding author of the study.
Innovative Approach to Drug Design
The research team, in collaboration with chemists from the Sanford Burnham Prebys Medical Discovery Institute (SBP), has devised a strategy to create compounds that selectively activate specific signaling pathways within the GPCRs. Unlike traditional GPCR-based drugs that target receptors externally, these new compounds bind to previously unexploited sites inside the cell, directly interacting with signaling partners.
In their experiments with the neurotensin receptor 1, a type of GPCR, the researchers discovered that these compounds could function as molecular glues, enhancing certain interactions, or as molecular bumpers, blocking others. This dual function allows for unprecedented control over the receptor’s signaling pathways.
“Most drugs ‘turn up’ or ‘turn down’ all of a receptor’s signaling uniformly,” Dr. Slosky explained. “In addition to ‘volume control,’ these new compounds change the message received by the cell.”
Predictable and Customizable Drug Profiles
Using advanced modeling techniques, the team designed compounds with diverse signaling profiles, resulting in varying biological effects. This approach allows scientists to predictably control which pathways are activated or inhibited by altering the compound’s chemical structure.
“We controlled which signaling pathways were turned on and which ones were turned off by changing the chemical structure of the compound,” said Steven Olson, PhD, the executive director of Medicinal Chemistry at SBP and study co-author. “Most importantly, these changes were predictable and can be used by medicinal chemists to rationally design new drugs.”
The implications of this research are vast. For the neurotensin receptor 1, the ultimate aim is to develop treatments for chronic pain and addiction that minimize side effects. Given that the intracellular site targeted by these compounds is common to the GPCR superfamily, this strategy could be adapted to develop therapies for a wide range of diseases.
Support and Future Directions
This study received support from several prestigious institutions, including the National Institutes of Health, the National Institute on Drug Abuse, the Department of Defense, the University of Minnesota Foundation, and various Japanese scientific agencies. The collaborative effort underscores the global significance of this research.
As the scientific community continues to explore the potential of GPCRs, the findings from this study offer a promising new direction in drug development. By enabling more precise control over receptor signaling, researchers can design medications that are not only more effective but also safer for patients. The future of pharmacology may well hinge on the continued exploration and application of these innovative techniques.
