β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation.

Abstract

BACKGROUND AND PURPOSE:

Asthma is a heterogenous disease strongly associated with inflammation that has many different causes and triggers. Current asthma treatments target symptoms such as bronchoconstriction and airway inflammation. Despite recent advances in biological therapies, there remains a need for new classes of therapeutic agents with novel, upstream targets. The proteinase-activated receptor-2 (PAR2) has long been implicated in allergic airway inflammation and asthma and it remains an intriguing target for novel therapies. Here, we describe the actions of C781, a newly developed low MW PAR2 biased antagonist, in vitro and in vivo in the context of acute allergen exposure.

EXPERIMENTAL APPROACH:

A human bronchial epithelial cell line expressing PAR2 (16HBE14o- cells) was used to evaluate the modulation in vitro, by C781, of physiological responses to PAR2 activation and downstream β-arrestin/MAPK and Gq/Ca2+ signalling. Acute Alternaria alternata sensitized and challenged mice were used to evaluate C781 as a prophylactically administered modulator of airway hyperresponsiveness, inflammation and mucus overproduction in vivo.

KEY RESULTS:

C781 reduced in vitro physiological signalling in response to ligand and proteinase activation. C781 effectively antagonized β-arrestin/MAPK signalling without significant effect on Gq/Ca2+ signalling in vitro. Given prophylactically, C781 modulated airway hyperresponsiveness, airway inflammation and mucus overproduction of the small airways in an acute allergen-challenged mouse model.

CONCLUSION AND IMPLICATIONS:

Our work demonstrates the first biased PAR2 antagonist for β-arrestin/MAPK signalling. C781 is efficacious as a prophylactic treatment for allergen-induced airway hyperresponsiveness and inflammation in mice. It exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development.

• Authors: Hillary V Schiff, Candy M Rivas, William P Pederson, Estevan Sandoval, Samuel Gillman, Joy Prisco, Moeno Kume, Gregory Dussor, Josef Vagner, Julie G Ledford, Theodore J Price, Kathryn A DeFea, Scott Boitano
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 180 Issue 5 Pg. 667-680 (03 2023) ISSN: 1476-5381 [Electronic] England
• PMID: 35735078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 British Pharmacological Society.

Chemical References

• Allergens
• Receptor, PAR-2
• beta-Arrestins
• beta-Arrestin 1

Topics

• Mice
• Humans
• Animals
• Allergens
• Receptor, PAR-2
• beta-Arrestins
• Asthma (drug therapy)
• Respiratory Hypersensitivity (drug therapy)
• beta-Arrestin 1
• Inflammation (drug therapy)
• Mice, Inbred BALB C
• Lung
• Bronchial Hyperreactivity (drug therapy)