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Review
. 2022 May 1;322(5):C887-C895.
doi: 10.1152/ajpcell.00449.2021. Epub 2022 Feb 23.

GPCR systems pharmacology: a different perspective on the development of biased therapeutics

Dylan Scott Eiger  1 , Uyen Pham  1 , Julia Gardner  2 , Chloe Hicks  2 , Sudarshan Rajagopal  1   3
Affiliations
Review

GPCR systems pharmacology: a different perspective on the development of biased therapeutics

Dylan Scott Eiger et al. Am J Physiol Cell Physiol. .

Abstract

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and are the target of approximately one-third of all Food and Drug Administration (FDA)-approved pharmaceutical drugs. GPCRs interact with many transducers, such as heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. Recent experiments have demonstrated that some ligands can activate distinct effector proteins over others, a phenomenon termed "biased agonism." These discoveries have raised the potential of developing drugs which preferentially activate therapeutic signaling pathways over those that lead to deleterious side effects. However, to date, only one biased GPCR therapeutic has received FDA approval and many others have either failed to meet their specified primary end points and or demonstrate superiority over currently available treatments. In addition, there is a lack of understanding regarding how biased agonism measured at a GPCR leads to specific downstream physiological responses. Here, we briefly summarize the history and current status of biased agonism at GPCRs and suggest adoption of a "systems pharmacology" approach upon which to develop GPCR-targeted drugs that demonstrate heightened therapeutic efficacy with improved side effect profiles.

Keywords: G protein-coupled receptor; biased agonism; drug development; systems pharmacology; β-arrestin.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

This article is part of the special collection “Advances in GPCRs: Structure, Mechanisms, Disease, and Pharmacology.” Wei Kong, MD, PhD, and Jinpeng Sun, PhD, served as Guest Editors of this collection.

Figures

Figure 1.
Figure 1.
Types of biased agonism observed at GPCRs. A: ligand bias—various ligands can bind to the same receptor but demonstrate differential activation of downstream transducers. The purple ligand (left) demonstrates a G protein-biased ligand, the pink ligand (middle) demonstrates a balanced ligand, and the yellow ligand (right) demonstrates a β-arrestin-biased ligand. B: receptor bias—some GPCRs demonstrate activation of β-arrestins over G proteins, or vice versa, irrespective of the bound ligand. Although the pink balanced ligand can activate both G proteins and β-arrestins at the blue GPCR, it demonstrates preferential activation of β-arrestins at the gray GPCR, as this receptor demonstrates receptor bias. C: systems bias—an unbiased ligand and unbiased receptor can generate a biased signaling response if the cellular system has unequal stoichiometries of signal effectors. D: location bias—GPCRs can exist at many subcellular locations and may demonstrate signaling profiles that are different from that observed at the plasma membrane. E: β-arrestins can adopt many conformations including a state bound to the GPCR core (“core” conformation), GPCR tail (“tail” conformation), or the GPCR tail whereas G proteins are simultaneously engaged with the GPCR core (“megaplex” conformation). These different conformations are related to specific β-arrestin-mediated signaling pathways. F: GPCRs are known to homo- or heterodimerize, as well as oligomerize. These multimeric structures can demonstrate signaling that is different from GPCR monomers. G: different ligands or GPCRs can activate the same effectors at different rates which can translate into different cellular responses. H: there are multiple G protein and β-arrestin isoforms which can simultaneously couple to a single GPCR. In addition to being biased with respect to G proteins and β-arrestins, a GPCR may demonstrate differentially coupling within each effector family. I: there are numerous other identified effectors that can couple to GPCRs, many of which may demonstrate biased behavior. GPCR, G protein-coupled receptor. AKAPS, A-kinase-anchoring protein.
Figure 2.
Figure 2.
A revised approach to the development of biased GPCR therapeutics. A: conventional approach to develop biased GPCR ligands: an endogenous or synthetic ligand demonstrates biased agonism at a GPCR, and this specific signaling is associated with a desired cellular or in vivo response. The signaling pathways responsible for the in vivo phenotype are largely considered as a black box. These compounds are then tested for the ability to generate the desired cellular or in vivo response. Medicinal chemistry or high throughput screening (HTS) is used to refine the ligand or identify other biased agonists which can then be tested at earlier stages in this approach. B: a systems pharmacology approach to develop biased GPCR ligands: a similar process is repeated as above; however, after the association between biased GPCR signaling and a desired cellular or in vivo phenotype is determined, multiple analyses are carried out to better define the signaling pathways that underlie the desired response. For example, methods include RNA-seq, mass spectrometry-based proximity labeling, proteomics, or phosphoproteomics, ChIP-seq, and RET-based biosensors. Identification of signaling pathways that associate with the desired phenotype can then serve as direct drug targets, or markers upon which to screen drug compounds. Similarly, the identified compounds using medicinal chemistry or HTS are then tested for their ability to generate the desired cellular or in vivo response, after which the process can be repeated and refined. ChIP-seq; chromatin immunoprecipitation sequencing; GPCR, G protein-coupled receptor; RET, resonance energy transfer.
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