New Molecular Strategies Enhance GPCR Drug Development Potential

Research from the University of Minnesota Medical School reveals that innovative molecules, termed “molecular bumpers” and “molecular glues,” can significantly alter the signaling pathways of G protein-coupled receptors (GPCRs). This advancement could pave the way for a new class of precision medicines, enhancing both safety and efficacy. The findings were published in the journal Nature on March 15, 2025.

Approximately one-third of all drugs approved by the Food and Drug Administration (FDA) target GPCRs, making them a vital area of pharmaceutical research. Despite their success, scientists believe that these receptors still possess untapped potential for developing new therapies. GPCRs can initiate multiple signaling pathways through 16 different G proteins, resulting in a variety of cellular and physiological responses. Some pathways offer therapeutic benefits, while others can lead to adverse side effects, complicating drug development.

Dr. Lauren Slosky, an assistant professor at the University of Minnesota Medical School and the lead author of the study, 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.

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 associated with GPCRs. Unlike traditional GPCR-targeting drugs that interact with receptors from outside the cell, these new compounds bind to a previously unexploited site on the intracellular side, engaging directly with signaling partners.

In their investigation of the neurotensin receptor 1, a specific GPCR, the team found that these compounds could function as both molecular glues, facilitating interactions with certain signaling partners, and molecular bumpers, inhibiting connections with others. Dr. Slosky elaborated, “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.”

Through modeling techniques, the researchers designed compounds with diverse signaling profiles, resulting in varying biological effects. Dr. Steven Olson, the executive director of Medicinal Chemistry at SBP and a co-author of the study, 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.”

The ultimate aim for targeting the neurotensin receptor 1 is to develop treatments for chronic pain and addiction that minimize unwanted side effects. Given that this intracellular site is common across the GPCR superfamily, the implications of this strategy could extend to many receptors, potentially leading to innovative therapies for a range of diseases.

The research marks a significant step in the pursuit of more precise and targeted treatments, emphasizing the need for continued exploration in the field of GPCR pharmacology. For further details, refer to the study by Madelyn N. Moore et al., “Designing Allosteric Modulators to Change GPCR G Protein Subtype Selectivity,” published in Nature (2025). DOI: 10.1038/s41586-025-09643-2.