Molecular bumpers and glues rewire GPCR signaling for next-generation drugs

New research led by the University of Minnesota School of Medicine shows that molecules that act 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 drugs. 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 therapies. These receptors can activate a multitude of signaling pathways downstream of 16 different G proteins, resulting in diverse cellular and physiological effects. Some of these pathways may be therapeutically useful, while others lead to undesirable side effects, limiting the potential for therapeutic development.

The ability to design drugs that produce only selected signaling effects may yield safer, more effective drugs. Until now, it wasn’t obvious how to do that.”

Lauren Slosky, PhD, assistant professor at the University of Minnesota Medical School, and the study’s senior and corresponding author

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

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

“Most drugs ‘turn up’ or ‘turn down’ all of a receptor’s signals equally,” said Dr. Slosky. “In addition to ‘tumor control,’ these new compounds change the message the cell receives.”

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

“We tested which signaling pathways were activated and which were deactivated by changing the chemical structure of the compound,” said Steven Olson, PhD, executive director of Medicinal Chemistry at SBP and co-author of the study. “More importantly, these changes were predictable and can be used by pharmaceutical chemists to rationally design new drugs.”

For the neurotensin 1 receptor, the ultimate goal is to discover treatments for chronic pain and addiction that minimize side effects. Because this intracellular location is common to the GPCR superfamily, this strategy is likely to be transferred to many receptors and may lead to new therapies for a wide range of diseases.

The study was supported by the National Institutes of Health, the National Institute on Drug Abuse, the Department of Defense, the University of Minnesota Foundation, the Japan Society for the Promotion of Science, the Japan Medical Research and Development Agency, and the Japan Science and Technology Agency.