About one-third of all drugs approved by the Food and Drug Administration (FDA) target the largest family of cell membrane receptors known as G protein-coupled receptors (GPCRs). These receptors are crucial for maintaining human health, playing a role in nearly every physiological function. Embedded in cell membranes, GPCRs detect a variety of biological signaling molecules outside the cell, activating proteins called G proteins and beta-arrestins inside the cell to execute numerous functions.
Despite the prevalence of GPCR-based drugs, scientists believe these receptors hold untapped potential for new treatments. Steven Olson, PhD, executive director of Medicinal Chemistry at the Sanford Burnham Prebys Medical Discovery Institute’s Center for Therapeutics Discovery, notes,
“Out of 826 GPCRs, approximately 165 are validated drug targets so many of them have not been drugged.”
Olson explains that the challenge lies in the binding pocket on the extracellular side, which can be too small, too large, or lack an obvious binding site. However, the intracellular side consistently binds G proteins or beta-arrestin, presenting a near-constant binding pocket.
New Insights into GPCR Signaling
Researchers from Sanford Burnham Prebys, the University of Minnesota, and Duke University published findings on October 22, 2025, in Nature, demonstrating how a small molecule can bind a GPCR inside the cell and specifically direct the receptor’s signaling. This discovery could allow drug designers to control signaling pathways, favoring therapeutic outcomes while avoiding unwanted side effects.
Lauren Slosky, PhD, an assistant professor of Pharmacology at the University of Minnesota and corresponding author of the study, states,
“People have understood the need for bias in drug design for a long time. These compounds, however, have been especially challenging to create because our understanding of how signaling bias is achieved is incomplete.”
The study reveals a new mechanism by which intracellular small molecules can confer signaling bias predictably, enabling rational drug design.
Understanding the Mechanisms
The research team focused on a GPCR called neurotensin receptor 1 (NTSR1) and a biased small molecule named SBI-553. They explored the sixteen G proteins and two beta-arrestin proteins activated by receptor signaling. Slosky explains,
“We quickly started to appreciate that the black-and-white view we’d had, which was that our compound turned the G proteins off and the beta-arrestin on, was way too simple.”
Instead, SBI-553 produced a range of activity levels across different G proteins and beta-arrestins.
Olson adds,
“When bound, SBI-553 serves as a molecular bumper blocking the typical way G proteins bind with NTSR1. It can also act as a molecular glue promoting the binding of certain subtypes of G protein that can achieve an alternative binding conformation.”
This understanding is crucial for designing compounds with precise activation of G proteins.
Implications for Drug Discovery
The potential of targeting NTSR1 for treating addiction and psychiatric disorders has been explored for decades, but severe side effects have hindered progress. Unlike unbiased compounds, SBI-553 avoids problematic side effects, including hypothermia and hypotension. The research team hypothesized that a particular G protein’s activation was responsible for these side effects. By fully inhibiting Gq, the suspected problem protein, SBI-553 demonstrated a safer profile.
Slosky notes,
“Unlike SBI-553, in mice treated with a balanced agonist, SBI-593 was unable to prevent hypothermia. In this case, a small change in the structure led to changes in signaling and biology.”
This highlights the importance of precise structural modifications in drug design.
Future Prospects
This breakthrough opens up possibilities for targeting previously “undruggable” receptors. By discovering molecules that bind to the intracellular site, researchers can predict molecular mechanisms responsible for bias, making them more manageable for drug discovery. Olson emphasizes,
“We’ve now shown that this intracellular site is druggable, and it opens up an enormous field of study.”
The predictability of these interactions is a significant factor for investment in drug discovery.
Madelyn Moore and Kelsey Person, graduate students in the Slosky lab at the University of Minnesota, share first authorship of the study. Additional contributors include Michael R. Jackson from Sanford Burnham Prebys and several researchers from the University of Minnesota, Duke University, and Tohoku University.
The study received support from various institutions, including the National Institutes of Health, the National Institute on Drug Abuse, and the Japan Society for the Promotion of Science, among others. The study’s DOI is 10.1038/s41586-025-09643-2.
