# Pharmacodynamics of Biased G Protein-Coupled Receptor Agonism

> **NIH NIH R35** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $373,750

## Abstract

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. Co...

## Key facts

- **NIH application ID:** 9916766
- **Project number:** 5R35GM126955-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** LOUIS M LUTTRELL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916766

## Citation

> US National Institutes of Health, RePORTER application 9916766, Pharmacodynamics of Biased G Protein-Coupled Receptor Agonism (5R35GM126955-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9916766. Licensed CC0.

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