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Abstract
The fact that over 30% of current pharmaceuticals target heptahelical G protein–coupled receptors (GPCRs) attests to their tractability as drug targets. Although GPCR drug development has traditionally focused on conventional agonists and antagonists, the growing appreciation that GPCRs mediate physiologically relevant effects via both G protein and non–G protein effectors has prompted the search for ligands that can "bias" downstream signaling in favor of one or the other process. Biased ligands are novel entities with distinct signaling profiles dictated by ligand structure, and the potential prospect of biased ligands as better drugs has been pleonastically proclaimed. Indeed, preclinical proof-of-concept studies have demonstrated that both G protein and arrestin pathway-selective ligands can promote beneficial effects in vivo while simultaneously antagonizing deleterious ones. But along with opportunity comes added complexity and new challenges for drug discovery. If ligands can be biased, then ligand classification becomes assay dependent, and more nuanced screening approaches are needed to capture ligand efficacy across several dimensions of signaling. Moreover, because the signaling repertoire of biased ligands differs from that of the native agonist, unpredicted responses may arise in vivo as these unbalanced signals propagate. For any given GPCR target, establishing a framework relating in vitro efficacy to in vivo biologic response is crucial to biased drug discovery. This review discusses approaches to describing ligand efficacy in vitro, translating ligand bias into biologic response, and developing a systems-level understanding of biased agonism in vivo, with the overall goal of overcoming current barriers to developing biased GPCR therapeutics.
Footnotes
- Received April 22, 2015.
- Accepted July 1, 2015.
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM095497], the National Institute of Diabetes, Digestive, and Kidney Diseases [Grant R01-DK055524], the Intramural Research Program of the National Institute on Aging, the National Institute on Drug Abuse [Grants R01-DA031927, R01-DA033073, P01-DA009158, and R01-DA038964], and the Research Service of the Charleston, SC Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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