Unlocking the potential of beta-arrestin isoform bias as a novel dimension of drug design - the overarching goal of this research program is to empower the research community to maximize the…

The National Institute of General Medical Sciences awarded the University of Wyoming $349,483 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support research unlocking the therapeutic potential of beta-arrestin isoform bias as a novel dimension of drug design targeting G protein-coupled receptors (GPCRs).

The research program addresses how GPCRs, which regulate nearly every physiological process in the body, initiate three distinct signaling cascades following agonist binding: G protein activation, beta-arrestin 1 recruitment, and beta-arrestin 2 recruitment (the latter two being mutually exclusive). The work leverages a novel drug screen demonstrating that GPCR agonists can bias the relative recruitment of the two beta-arrestin isoforms, opening the possibility of designing pharmaceuticals with established or new therapeutic effects while minimizing deleterious side effects from undesirable signaling pathways. Current drug development efforts often fail to account for the distinct and frequently opposing roles these beta-arrestin isoforms play in disease models. The program aims to empower the research community to harness the full three-pronged GPCR signal transduction mechanism by incorporating beta-arrestin isoform selectivity into biased agonist design.

Performance occurs at the University of Wyoming in Laramie, Wyoming. The award period runs from September 1, 2026, through April 30, 2031. This is a Project Grant, the assistance type supporting investigator-initiated biomedical research.

Unlocking the potential of beta-arrestin isoform bias as a novel dimension of drug design - the overarching goal of this research program is to empower the research community to maximize the therapeutic potential of g protein-coupled receptors (gpcrs), a ubiquitous family of proteins that play crucial roles in nearly every physiological process in the body. Broadly speaking, the consequences of gpcr signaling begin at three events following agonist binding: the activation of g proteins, the recruitment of -arrestin 1, and the recruitment of its isoform -arrestin 2, the latter two of which are mutually exclusive in that a gpcr can only bind a single -arrestin at a time. These three prongs of gpcr signal transduction each represent the start of an ever-widening signaling cascade inside the cell and often mediate distinct physiological and/or behavioral consequences of gpcr activation. The discovery that "biased" agonists can direct gpcr signaling preferentially via g proteins or β-arrestins opened the possibility of designing next-generation pharmaceuticals that have established or new therapeutic effects while lacking deleterious "side effects" that result from the activation of undesirable pathways. However, many of these efforts do not account for the distinct and often opposing roles β-arrestin isoforms can play in disease models. To take full advantage of the therapeutic potential of gpcrs, biased agonist design would therefore ideally account for differences in β-arrestin isoform signaling. This nigms-related research program leverages a novel drug screen which demonstrated that gpcr agonists can bias the relative recruitment of the two -arrestin isoforms. This unappreciated level of control gpcrs have over their signaling offers an opportunity for the research community to harness the full power of the three-pronged gpcr signal transduction mechanism. Given gpcrs' biological importance and the different roles of the -arrestin isoforms in mediating their effects, this work has profound implications for designing drugs with improved effect profiles across numerous biomedical fields. Using the delta opioid receptor (or) as a model system, the program's research goals over the next five years are to measure -arrestin isoform bias robustness to -arrestin and gpcr expression conditions, determine which protein residues are essential for -arrestin isoform bias, and measure the impact of -arrestin isoform bias on or trafficking, cellular signaling, and or-induced behavioral effects. To facilitate the world- wide exploration of -arrestin isoform bias, a further goal is to develop and disseminate a high-throughput drug screen for quantifying -arrestin isoform bias at every non-olfactory gpcr. The overall vision of the research program is that the proposed work in understanding -arrestin isoform bias will lead to significant advancements in how researchers develop therapeutics with improved effect profiles. Thus, this research program aligns well with the goal of nigms to support basic research that increases understanding of biological processes and lays the foundation for advances in disease treatment.