New Molecules Offer Safer Routes to Precision Medicines

Research from the University of Minnesota Medical School has unveiled promising advancements in precision medicine through the development of molecules known as “molecular bumpers” and “molecular glues.” These novel compounds have the potential to finely tune the signaling of G protein-coupled receptors (GPCRs), which are pivotal in drug design and therapeutic applications. This groundbreaking study, published on March 15, 2024, in the journal Nature, highlights a significant step toward safer and more effective medications.

Approximately one-third of all drugs approved by the Food and Drug Administration (FDA) target GPCRs. Although these receptors represent a major class of drug targets, researchers believe that many of their signaling pathways remain underutilized for therapeutic development. GPCRs can activate various signaling pathways through 16 distinct G proteins, leading to diverse cellular effects. Some pathways could be leveraged for therapeutic gains, while others may result in adverse side effects that complicate treatment efficacy.

Dr. Lauren Slosky, an assistant professor at the University of Minnesota Medical School and the lead author of the study, noted, “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.” The research team, collaborating with chemists from the Sanford Burnham Prebys Medical Discovery Institute, has devised a strategy to design compounds that selectively activate specific signaling pathways within GPCRs.

Traditionally, GPCR-targeting drugs interact with receptors from the outside of the cell. The new compounds, however, bind to an unexplored site on the inside of the cell, forming direct interactions with signaling partners. The study focused on the neurotensin receptor 1, a specific type of GPCR, and revealed that compounds binding to this intracellular site could function as molecular glues—facilitating some interactions while acting as molecular bumpers to inhibit others.

Dr. Slosky explained the innovative approach: “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 advanced modeling, the research team was able to create compounds with varied signaling profiles, resulting in different biological consequences.

Co-author Dr. Steven Olson, the executive director of Medicinal Chemistry at SBP, emphasized the predictability of these modifications, stating, “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 the neurotensin receptor 1 is to develop treatments for chronic pain and addiction while minimizing side effects. Given that this intracellular binding site is common across the GPCR superfamily, the implications of this research extend to multiple receptors, potentially leading to innovative treatments for a variety of diseases.

The findings of this study represent a significant advancement in drug design, opening new possibilities for the development of precision medicines that prioritize safety and efficacy. As researchers continue to explore these molecular strategies, the future may hold a new paradigm in the treatment of complex health conditions.

For further details, refer to the original study by Madelyn N. Moore et al. in Nature.