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

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.

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

“…After GPCR is stimulated by extracellular signals, activated GPCR can induce structural rearrangement of its cytoplasmic region ( 199 ) and induce intracellular signal transduction through classical G protein or GRK-arrestin pathway ( Figure 2 ) ( 200 , 201 ), and this signal transduction can be biased in three ways. System bias refers to the differential expression of signaling pathways of the same receptor or ligand in a different time, space, and cell type.…”

Adrenoceptor Desensitization: Current Understanding of Mechanisms

“…What also supports this therapeutic idea is that balanced β 2 -AR agonists run the risk of therapeutic tolerance or loss of response with prolonged treatment, as data suggests that desensitization and downregulation of β 2 -ARs occurs downstream of β-Arr binding (Gagnon et al, 1998). Moreover, these drugs have been the subject of much scrutiny due to the increased risk of asthma morbidity/mortality associated with their chronic usage (Kim et al, 2021;Tokmakova et al, 2022). More recently, it was shown that adrenaline-dependent β 2 -AR signaling activation is required for the development of the asthma phenotype in an allergen-driven (Ova S/C) murine asthma model, and chronic treatment with various β-blockers has yielded conflicting results, likely due to drug-specific biased signaling (Thanawala et al, 2013;Thanawala et al, 2015) Recent evidence demonstrates critical roles for post-translational modifications other than phosphorylation in intracellular signaling.…”

Adrenergic signaling regulation of macrophage function: do we understand it yet?

“…One can easily find reports that compare the effects of different types of β2AR agonists (mainly short acting vs long acting) on the bronchia [ 82 , 83 ], but comparative studies that focus on the effects of the different agonists in lung inflammation are lacking, mainly the ones focused on immunological and molecular mechanisms. Still, the notion that biased agonists (agonist that preferentially triggers a downstream molecular pathway; i.e., carvedilol, a β2AR agonist that preferentially triggers β-arrestin signaling instead of cAMP-dependent signaling after [ 84 ]) can produce different clinical outcomes is starting to get more attention in different disease models [ 85 , 86 ]. There are interesting research paths to be pursued in this issue.…”