Research led by the University of Minnesota Medical School reveals innovative molecules known as “molecular bumpers” and “molecular glues” that can modify signaling pathways of G protein-coupled receptors (GPCRs). This breakthrough has the potential to convert these highly active cellular receptors into precision tools for drug development, paving the way for a new class of safer and more effective medications. The findings were published in the journal Nature.
GPCRs represent a significant target in pharmacology, with approximately one-third of drugs approved by the Food and Drug Administration designed to interact with this receptor family. Despite their success, researchers believe there remains considerable unrealized potential within these receptors for therapeutic applications. GPCRs can influence numerous signaling pathways via 16 different G proteins, leading to various cellular responses. Some of these effects can be beneficial for treatment, while others may result in adverse side effects that hinder therapeutic advancements.
“Designing drugs that selectively activate desired signaling pathways may lead to safer and more efficacious treatments. Until now, achieving this has been challenging,” stated Lauren Slosky, Ph.D., an assistant professor and the lead author of the study.
The research team, which included chemists from the Sanford Burnham Prebys Medical Discovery Institute (SBP), developed a novel strategy for creating compounds that specifically activate certain signaling pathways associated with GPCRs. Unlike conventional GPCR-targeting drugs that interact with the receptor from the outside, these new compounds attach to an unexploited site located within the cell. This allows them to engage directly with signaling partners.
In their analysis of the neurotensin receptor 1, a specific GPCR, the team discovered that compounds binding to this intracellular site could function as molecular glues, enhancing interactions with selected signaling partners, while simultaneously acting as molecular bumpers that inhibit connections with others. “Most pharmaceuticals either increase or decrease signaling uniformly across all pathways,” Dr. Slosky explained. “These new agents can alter the message the cell receives beyond simple volume adjustments.”
Using computational models, the researchers were able to create compounds with varied signaling profiles, resulting in distinct biological outcomes. “By modifying the chemical structure of the compounds, we could determine which signaling pathways would be activated or suppressed,” said Steven Olson, Ph.D., the executive director of Medicinal Chemistry at SBP and a co-author of the study. “Crucially, these modifications were systematic, providing a framework for medicinal chemists to rationally design new drugs.”
For the neurotensin receptor 1, the ultimate aim is to develop treatments for chronic pain and addiction that minimize adverse effects. Given that this intracellular binding site is prevalent across the GPCR superfamily, this innovative approach could be applied to a wide range of receptors, potentially leading to novel therapies for various diseases.
More information on this research can be found in the study titled “Designing allosteric modulators to change GPCR G protein subtype selectivity” published in Nature.
