Recent research from the University of Minnesota Medical School reveals that innovative molecules, referred to as “molecular bumpers” and “molecular glues,” can significantly reshape the signaling of G protein-coupled receptors (GPCRs). These findings, published in the journal Nature, suggest a promising pathway for developing safer and more targeted medications, potentially revolutionizing treatment options for various conditions.
GPCRs represent a critical class of drug targets, with approximately one-third of drugs approved by the Food and Drug Administration targeting this family. Despite their success, researchers believe that GPCRs still have untapped potential for new therapeutic developments. These receptors can activate multiple downstream signaling pathways through 16 different G proteins, leading to diverse cellular effects. While some pathways may offer therapeutic benefits, others can cause undesired side effects, which complicates the development of effective treatments.
The lead author of the study, Lauren Slosky, Ph.D., an assistant professor at the University of Minnesota Medical School, emphasized the significance of this research. “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,” she stated.
Innovative Strategies for Drug Design
The research team, which included chemists from the Sanford Burnham Prebys Medical Discovery Institute (SBP), developed a strategy to create compounds that selectively activate specific signaling pathways of GPCRs. Unlike traditional GPCR-targeting drugs that interact with receptors from outside the cell, these new compounds bind to a previously unaddressed site within the cell, allowing for direct interaction with key signaling partners.
In their examination of the neurotensin receptor 1, a particular type of GPCR, the researchers found that these compounds could function both as molecular glues—facilitating interactions with certain signaling partners—and as molecular bumpers—preventing interactions with others. Dr. Slosky explained, “Most drugs ‘turn up’ or ‘turn down’ all of a receptor’s signaling uniformly. In addition to ‘volume control,’ these new compounds change the message received by the cell.”
Using advanced modeling techniques, the team designed compounds with distinct signaling profiles, resulting in varying biological impacts. Co-author Steven Olson, Ph.D., the executive director of Medicinal Chemistry at SBP, noted, “We controlled which signaling pathways were turned on and which ones were turned off by changing the chemical structure of the compound. Most importantly, these changes were predictable and can be used by medicinal chemists to rationally design new drugs.”
Potential Applications in Medicine
The ultimate goal of this research is to develop effective treatments for chronic pain and addiction that minimize unwanted side effects. Since the intracellular site targeted by the new compounds is common across the GPCR superfamily, this innovative strategy is likely applicable to a wide range of receptors. As a result, it may pave the way for novel therapies addressing numerous diseases.
The study’s findings represent a significant advancement in the field of pharmacology, offering hope for creating more precise and effective medications. As researchers continue to explore the capabilities of molecular bumpers and glues, the potential for improving patient outcomes across various health conditions remains promising.
For further details, refer to the study: Madelyn N. Moore et al, “Designing allosteric modulators to change GPCR G protein subtype selectivity,” Nature, 2025. DOI: 10.1038/s41586-025-09643-2.