Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease.

Alina Tokmakova,Stephen B. Liggett,Donghwa Kim,William A. Goddard

doi:10.3390/jpm12030331

Abstract

Signals from G-protein-coupled receptors (GPCRs) are the most frequently targeted pathways of currently prescribed therapeutics. Rather than being a simple switch, it is now evident that a given receptor can directly initiate multiple signals, and biasing to achieve signal selectivity based on agonist structure is possible. Biased agonists could direct therapeutically favorable pathways while avoiding counterproductive or adverse reaction pathways. For obstructive lung diseases, β2-adrenergic receptor (β2AR) agonists act at these receptors on airway smooth muscle (ASM) cells to open the airways by relaxing ASM, improving airflow and morbidity. However, these receptors signal to the G protein Gs (increasing cAMP and promoting relaxation), but also to β-arrestin (promoting desensitization and a loss of effectiveness). Indeed, β-agonist use is associated with adverse events in asthma pathogenesis and clinical outcomes which are related to desensitization. β-agonists favoring Gs coupling over β-arrestin binding would provide a means of tailoring bronchodilator therapy. In this review, we show how combinatorial methods with a 40 million compound agnostic library led to a new class of biased β-agonists that do not desensitize, providing an opportunity to personalize therapy in patients who experience poor efficacy or adverse effects from traditional balanced agonists.

Highlights

G-protein-coupled receptor (GPCR) proteins represent the largest superfamily of proteins in the body, each with seven transmembrane helices spanning the lipid bilayer
Most GPCRs display a rapid attenuation of signaling with continuous agonist activation, termed desensitization, which is thought to be a mechanism of fine-tuning the response in cells that are receiving hundreds of receptor signals [1]
The G-proteincoupled receptor kinases (GRKs)-phosphorylated receptor is a substrate for the binding of arrestins, which interdict between receptor and G protein, causing a partial loss of signaling

Summary

Introduction

G-protein-coupled receptor (GPCR) proteins represent the largest superfamily of proteins in the body, each with seven transmembrane helices spanning the lipid bilayer. For Class A GPCRs, agonist binding occurs within a pocket formed by the upper portions (extracellular ends) of the TMDs and the ECLs. GPCRs transduce signaling by coupling to heterotrimeric G proteins, consisting of α, β, and γ subunits. In the traditional model of signaling, agonist activation results in the binding of the receptor to the α subunit of the G protein, with the subsequent dissociation of the heterotrimer into the α and βγ subunits. Most GPCRs display a rapid attenuation of signaling with continuous agonist activation, termed desensitization, which is thought to be a mechanism of fine-tuning the response in cells that are receiving hundreds of receptor signals [1]. The most rapid form of agonist-promoted desensitization is mediated by the phosphorylation of intracellular Ser or Thr by G-proteincoupled receptor kinases (GRKs). As will be further discussed in the context of biased agonism, arrestins promote additional regulatory events during more prolonged agonist activation, and they evoke de novo signals that are independent of the G protein

Biased Agonist Signaling at GPCRs

Findings

Ascertainment of Gs-Biasing with Selected Compounds