Pharmacodynamics of Biased G Protein-Coupled Receptor Agonism

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While G protein-coupled receptor (GPCR) drug development has traditionally focused on conventional agonism and antagonism, the newer paradigms of `pluridimensional efficacy' and `functional selectivity' recognize that GPCRs mediate biological effects through both classical G protein-dependent and novel G protein-independent signaling networks, and that ligand structure can `bias' signaling by stabilizing active receptor states in different proportions than the native ligand. Such `biased agonists' are novel entities that possess pathway-selective efficacy, in effect creating new receptors with distinct signaling profiles driven by ligand structure. The promise of biased agonism resides with this ability to engender mixed agonist/antagonist effects in vivo and produce biological effects not attainable with conventional agonists or antagonists. Recent experience has shown, however, that biased agonist effects in vivo are often unpredictable, indicating that key gaps exist in our understanding of biased agonism that stand as barriers to the rational design of novel GPCR targeted therapeutics. Progress in our laboratory over the past five years has provided some mechanistic insights into the apparent idiosyncratic nature of ligand bias. We have shown that ligand structure can specify distinct `activation modes' in effectors, causing the same effector to perform different functions and even dissociating classically linked effector functions, e.g. arrestin-dependent GPCR desensitization and signaling. As these `unbalanced' signals propagate, we find that biased agonists can sometimes produce opposite effects on downstream signaling networks than conventional agonists. As a result, the in vivo transcriptomic `fingerprint' of biased and conventional agonists are largely non-overlapping at the level of regulated signaling pathways and biological processes. Fortunately, in the case of arrestin pathway-selective bias it appears that the arrestin-dependent signaling repertoire is sufficiently restricted that the transcriptomic effects are relatively conserved between tissues and focused on regulation only a few basic biological processes. The overall objectives of our future research are: 1) to understand the mechanisms underlying biased GPCR signaling at the molecular level so as to better predict how different forms of ligand bias will change the cellular response to GPCR activation; and, 2) to determine how biased efficacy measured in engineered `screening' cell systems relates to the biological responses they produce in physiologically relevant cells and tissues. As in the past, we will employ a full range of cell-based techniques to characterize the impact of ligand structure on receptor and effector conformation and function, as well as systems level bioinformatics analysis of proteomic and transcriptomic datasets to determine how specific patterns of efficacy impact the behavior of primary cells and the influence of cell background on the response. Completion of this project will help to develop a rational framework for relating in vitro ligand efficacy to the in vivo actions of arrestin pathway-selective biased GPCR ligands, providing information and tools that are critical to the development of novel biased therapeutics.