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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 biologic therapies, there remains a need for new classes of therapeutics with novel, upstream targets. Proteinase-activated receptor-2 (PAR2) has long been implicated in allergic airway inflammation and asthma and it remains an intriguing target for novel therapies. In this study we describe the newly developed small molecule PAR2 biased antagonist C781 in vitro and in vivo in the context of acute allergen exposure. Experimental Approach: A human bronchial epithelial cell line that naturally expresses PAR2 (16HBE14o- cells) was used to evaluate the ability for C781 to mediate in vitro PAR2 physiological response and downstream β-arrestin/MAPK and Gq/Ca2+ signalling. Acute Alternaria alternata sensitized and challenged mice were used to evaluate the ability for C781 to prophylactically mediate airway hyperresponsiveness, inflammation and mucus overproduction in vivo. Key Results: C781 was effective in reducing 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 effectively mediated airway hyperresponsiveness, airway inflammation and mucus overproduction of the small airways in an acute allergen-challenged mouse model. Conclusions 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 and thus, exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development.

Original languageEnglish (US)
JournalBritish Journal of Pharmacology
DOIs
StateAccepted/In press - 2022

Keywords

  • C781
  • Ca signalling
  • asthma
  • inflammation
  • β-arrestin/MAPK signalling

ASJC Scopus subject areas

  • Pharmacology

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