A groundbreaking study led by the University of Minnesota Medical School has revealed that molecules functioning as “molecular bumpers” and “molecular glues” can significantly modify the signaling of G protein-coupled receptors (GPCRs). This innovation transforms the most active cell receptors into precise instruments for drug development, potentially paving the way for a new class of safer and more effective medications. The findings were published in the journal Nature.
Approximately one-third of all medications approved by the Food and Drug Administration (FDA) target the GPCR family. Despite being the largest and most successful category of drug targets, these receptors still present unexplored opportunities for developing new therapies. They can trigger a wide range of signaling pathways through 16 distinct G proteins, leading to various cellular responses. While some of these pathways could be beneficial for treatment, others may result in undesirable side effects, which can hinder therapeutic advancements.
“The ability to create drugs that selectively produce specific signaling outcomes holds the promise of yielding safer and more effective therapies. Until now, achieving this has been a challenge,” stated Lauren Slosky, Ph.D., an assistant professor at the University of Minnesota Medical School and the lead author of the study.
The research team, which included chemists from the Sanford Burnham Prebys Medical Discovery Institute, outlined a novel approach for designing compounds that selectively activate certain normal signaling pathways of the receptors. Unlike most existing GPCR-targeted drugs that interact with receptors from outside the cell, these new compounds attach to a previously untargeted site within the cell. This allows them to directly engage with signaling partners.
In their investigation of the neurotensin receptor 1, a particular type of GPCR, the researchers discovered that compounds binding to this intracellular site could function as molecular glues, facilitating interactions with some signaling partners, while acting as molecular bumpers, inhibiting interactions with others. “Conventional drugs typically amplify or reduce all of a receptor”s signals uniformly,” Dr. Slosky explained. “In contrast, these new compounds not only adjust the “volume” but also alter the messages sent to the cell.”
Through advanced modeling, the team engineered new compounds exhibiting a variety of signaling profiles, resulting in differing biological effects. “By modifying the chemical structure of the compounds, we could control which signaling pathways were activated and which were suppressed,” noted Steven Olson, Ph.D., executive director of Medicinal Chemistry at SBP and a co-author of the study. “These modifications were not just random; they were predictable and can inform medicinal chemists in their drug design efforts.”
For the neurotensin receptor 1, the ultimate aim of this research is to develop treatments for chronic pain and addiction while minimizing side effects. Given that this intracellular site is prevalent across the GPCR superfamily, this innovative strategy has the potential to be applicable to numerous receptors and could lead to new treatment modalities for a broad spectrum of diseases.
For more information, see: Madelyn N. Moore et al, Designing allosteric modulators to change GPCR G protein subtype selectivity, Nature (2025). DOI: 10.1038/s41586-025-09643-2
