Development of Gs‐biased modulators of the β2‐adrenergic receptor (662.1)

Asthma is a complex disease that is manifested by enhanced airway inflammation that leads to airway smooth muscle (ASM) contraction and airway constriction. While β‐agonists serve as a major asthma therapeutic, these drugs may also increase the risk of having a severe asthmatic attack that can result in death. Since several lines of evidence suggest that β 2 AR interaction with β‐arrestins may play a role in these adverse effects, biased ligands that selectively promote β 2 AR interaction with Gs may serve as an effective way of treating asthma. While an orthosteric Gs‐biased agonist for the β 2 AR has yet to be identified, another strategy to stabilize the conformation of a G protein‐coupled receptor (GPCR) is to target the intracellular surface of the receptor using pepducins. Pepducins are lipidated peptides derived from the intracellular domains of a GPCR. A library of β 2 AR pepducins was synthesized and screened for cAMP production and β‐arrestin recruitment and identified two classes of Gs‐biased pepducins: receptor‐dependent and receptor‐independent. The Gs‐biased pepducins exhibit minimal functional desensitization in cells and do not induce GPCR kinase (GRK) phosphorylation or internalization of the β 2 AR, although PKA‐mediated phosphorylation was observed. The receptor‐independent pepducins appear to directly activate Gs while the receptor‐dependent pepducins promote cAMP production that is sensitive to the inverse agonist ICI 118,551, suggesting that the pepducin is stabilizing a Gs‐biased conformation of the β 2 AR. These pepducins represent the first reported Gs‐biased modulators and offer a potential new class of asthma therapeutics. Grant Funding Source : Supported by P01HL114471 (NHLBI) and T32GM100836 (NIGMS)