Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

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 pathwayselective 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 systemslevel understanding of biased agonism in vivo, with the overall goal of overcoming current barriers to developing biased GPCR therapeutics.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

“…THC and CP treatment promote b-arrestin-dependent CB 1 internalization and reduce CB 1 -dependent downstream signaling (Laprairie et al, 2014). Functional selectivity (i.e., signaling bias) describes the receptor-and ligand-dependent enhancement of certain signal transduction pathways and the simultaneous diminution of other signal transduction pathways at a single receptor (Luttrell et al, 2015). Functional selectivity occurs via a GPCR ligand that preferentially activates one effector (e.g., Ga i/o ) more potently and efficaciously than another (e.g., b-arrestin) through ligand-specific changes in GPCR conformation or dimerization with other GPCRs (Christopoulos, 2014).…”

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…Although this is poorly explored, these differences may reflect the relative prevalence of distinct G protein-mediated and noncanonical pathways that a receptor can couple to in different cell types. Importantly, such variation expands the diversity and utility of endogenous ligands and their receptors (Thompson et al, 2014) beyond the currently fashionable view of "biased" ligands that favor engagement with one signaling pathway over another in a single cell type (Violin et al, 2014;Luttrell et al, 2015). FFA4 is such a pleotropic GPCR (Milligan et al, 2015), able to generate a range of physiologic endpoints in different cell types by engaging distinct signaling pathways.…”

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

“…This cell system is certainly far from representing the physiological context of GHS-R1a-dependent signaling. Furthermore, the selectivity of action of ligands on various signaling pathways varies depending on the cellular context (60,61). Therefore, before drawing any definitive conclusions on the physiological reality of the signaling selectivity of our ligands that was only observed so far in HEK293, further studies should be carried out in other heterologous cell systems, or even better in primary cells that endogenously express the GHS-R1a.…”