A groundbreaking study from the University of Minnesota Medical School has unveiled how certain molecules, referred to as “molecular bumpers” and “molecular glues,” can modify the signaling of G protein-coupled receptors (GPCRs). This innovation could pave the way for a new class of safer and more precise medications. The research findings were published in the journal Nature.
GPCRs are vital targets for drug development, representing approximately one-third of all medications approved by the Food and Drug Administration. Despite their success, scientists believe that the full potential of these receptors remains largely unexplored. GPCRs can activate numerous signaling pathways through 16 different G proteins, which can result in varying cellular responses. While some pathways may have therapeutic benefits, others can lead to undesirable side effects, hindering the development of effective treatments.
“The ability to create drugs that selectively activate certain signaling outcomes could lead to more effective and safer medications. Until now, achieving such precision has been challenging,” stated Lauren Slosky, Ph.D., an assistant professor at the University of Minnesota Medical School and the study”s senior author.
The research team, which included chemists from the Sanford Burnham Prebys Medical Discovery Institute, introduced a new method for designing compounds that specifically target a limited range of a receptor”s signaling pathways. Unlike most existing GPCR-targeting drugs that interact with the receptor from outside the cell, these innovative compounds bind to a previously unexploited site within the cell, allowing for direct interaction with signaling partners.
In their investigation of the neurotensin receptor 1, a specific type of GPCR, the researchers discovered that compounds attaching to this intracellular receptor site can function as molecular glues, enhancing interactions with certain signaling partners, while also acting as molecular bumpers that inhibit interactions with others. “Traditionally, drugs either increase or decrease the overall signaling of a receptor. These new compounds can modulate the specific message that the cell receives,” Dr. Slosky explained.
The research team utilized computational modeling to create compounds with varied signaling profiles, resulting in distinct biological effects. “By altering the chemical structure of the compounds, we were able to control which signaling pathways were activated and which were suppressed,” noted Steven Olson, Ph.D., the executive director of Medicinal Chemistry at SBP and a co-author of the study. “Importantly, these modifications were predictable and can inform medicinal chemists in the rational design of new pharmaceuticals.”
For the neurotensin receptor 1, the ultimate aim is to develop therapies for chronic pain and addiction that minimize adverse effects. Given that this intracellular site is prevalent across the GPCR superfamily, this innovative strategy has the potential to be applicable to a wide range of receptors, possibly leading to new treatments for numerous diseases.
For further details, refer to the study by Madelyn N. Moore et al., titled “Designing allosteric modulators to change GPCR G protein subtype selectivity,” published in Nature.
