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New research led by the University of Minnesota Medical School demonstrates that molecules acting as “molecular bumpers” and “molecular glues” can rewire G protein-coupled receptor (GPCR) signaling, turning the cell’s busiest receptors into precision tools—opening the door to a new generation of safer, smarter medicines. The findings were published today in Nature.

About one-third of all drugs approved by the Food and Drug Administration target the GPCR family. Although they are the largest family of successful drug targets, scientists recognize that these receptors still hold untapped potential as targets for new treatments. These receptors can activate a plethora of signaling pathways downstream of 16 different G proteins, resulting in different cellular and physiological effects. Some of these pathways may be therapeutically useful, while others lead to unwanted side effects, limiting the potential for therapeutic 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, Ph.D., an assistant professor at the University of Minnesota Medical School, and the senior and corresponding author of the study.

In this study, the research team, including chemists at the Sanford Burnham Prebys Medical Discovery Institute (SBP), describe a strategy to design compounds that selectively activate a subset of the receptor’s normal signaling pathways. Nearly all other GPCR-based drugs target the receptor from outside the cell. These new compounds bind a previously undrugged site on the inside of the cell. Here, they directly interact with signaling partners.

In their study of the neurotensin receptor 1, a type of GPCR, the research team found that compounds binding this intracellular receptor site can act as molecular glues—promoting interactions with some signaling partners—and as molecular bumpers, preventing interactions with other signaling partners.

“Most drugs ‘turn up’ or ‘turn down’ all of a receptor’s signaling uniformly,” Dr. Slosky said. “In addition to ‘volume control,’ these new compounds change the message received by the cell.”

Using modeling, they designed new compounds with diverse signaling profiles, leading to different biological effects.

“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, Ph.D., 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.”

For the neurotensin receptor 1, the ultimate goal is to discover treatments for chronic pain and addiction that minimize side effects. Because this intracellular site is common to the GPCR superfamily, this strategy is likely transferable to many receptors and may lead to novel treatments for a wide array of diseases.

More information: Madelyn N. Moore et al, Designing allosteric modulators to change GPCR G protein subtype selectivity, Nature (2025). DOI: 10.1038/s41586-025-09643-2

Journal information: Nature

Citation: ‘Molecular glues’ and ‘bumpers’ offer new hope for precision medicines (2025, November 2) retrieved 2 November 2025 from https://medicalxpress.com/news/2025-11-molecular-bumpers-precision-medicines.html

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