ΒETA-ARRESTIN-BIASED PROTEASE-ACTIVATED RECEPTOR-2 ANTAGONIST C781 LIMITS ALLERGEN-INDUCED AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION

Abstract

Millions of patients in the United States suffer from asthma, and of these patients 5-10% are estimated to have a disease state that remains uncontrolled by current treatments. Therefore, there is a strong need for advances in allergic asthma medications. Protease-activated-Receptor 2 (PAR2) as expressed in the airway has been implicated in allergic asthma through its paradoxical downstream signaling pathways. The β-arrestin-dependent pathway promotes inflammation, while the Gαq-dependent pathway has a protective effect, promoting relaxation. We have developed a biased PAR2 antagonist C781 that selectively blocks the β-arrestin-dependent inflammatory pathway, and that we have shown to be promising in vivo to attenuate asthma indicators in an acute allergen exposure model in mice. In this thesis, the landscape of current asthma treatments is explored, and the logic behind the development of C781 is established. Next, we describe the efficacy of C781 in vitro cell-based assays and in vivo mouse models as published in the British Journal of Pharmacology. We conclude by exploring future directions in the development of PAR2 biased antagonists with the potential for biochemical optimization of C781.