Beta-arrestin-biased protease-activated receptor-2 antagonists preferentially limit allergen-induced responses in vivo.

Abstract

Biased signaling in G protein-coupled receptors (GPCRs) has emerged as a target for drug development. Protease-activated receptor-2 (PAR2) is a GPCR present in the airway epithelium with biased signaling that has been shown to trigger both detrimental effects [airway hyperresponsiveness (AHR), inflammation, mucus overproduction] and beneficial effects (bronchorelaxation) associated with allergen-induced asthma. These dual effects have been shown to be dictated by the two primary signaling pathways downstream of PAR2 activation: Gαq/Ca 2+ signaling is associated with bronchorelaxation, and β-arrestin/MAPK signaling is associated with AHR, inflammation and mucus overproduction. We have developed full (C391 which antagonizes Gαq/Ca 2+ and β-arrestin/MAPK signaling) and biased (C781 which antagonizes β-arrestin/MAPK signaling) antagonists of PAR2 and tested their efficacy in acute allergen-induced asthma mouse models. Both full and β-arrestin/MAPK signaling compounds attenuated AHR and inflammation in mouse models, and to a lesser extent, mucus overproduction. In a human bronchial model, the full PAR2 antagonist C391 prevented PAR2- dependent bronchial relaxation while the biased PAR2 antagonist C781 did not. Antagonism by C781 and other biased PAR2 antagonists can fine tune and effectively improve safety profiles for drug development in asthma treatment. Grants from the National Institute of Health (NS098826, AI140257, HL16024, HL152942) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.