Asthma and Airway Disease Research Center, University of Arizona Health Sciences Center, Tucson, Arizona, USA.
Bio5 Collaborative Research Center, University of Arizona, Tucson, Arizona, USA.
Br J Pharmacol. 2023 Mar;180(5):667-680. doi: 10.1111/bph.15903. Epub 2022 Dec 5.
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.
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/Ca 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.
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/Ca 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.
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.
哮喘是一种与炎症密切相关的异质性疾病，其病因和诱因很多。目前的哮喘治疗方法针对支气管收缩和气道炎症等症状。尽管生物治疗最近取得了进展，但仍需要具有新作用机制的新型治疗药物。蛋白酶激活受体-2（PAR2）长期以来一直与过敏性气道炎症和哮喘有关，它仍然是新型治疗方法的一个有趣的靶点。在这里，我们描述了新开发的低分子量 PAR2 偏向性拮抗剂 C781 在急性过敏原暴露情况下的体外和体内作用。
使用表达 PAR2 的人支气管上皮细胞系（16HBE14o-细胞）评估 C781 在体外对 PAR2 激活及下游β-arrestin/MAPK 和 Gq/Ca 信号的生理反应的调节作用。急性 Alternaria alternata 致敏和挑战的小鼠用于评估 C781 作为预防性给药调节剂对气道高反应性、炎症和粘液过度产生的体内作用。
C781 减少了配体和蛋白酶激活时的体外生理信号。C781 有效地拮抗了β-arrestin/MAPK 信号，而对体外的 Gq/Ca 信号没有显著影响。预防性给予 C781 可调节急性过敏原挑战小鼠模型中的气道高反应性、气道炎症和小气道粘液过度产生。
我们的工作证明了第一个针对β-arrestin/MAPK 信号的偏向性 PAR2 拮抗剂。C781 作为一种预防性治疗药物，可有效治疗小鼠过敏原诱导的气道高反应性和炎症。它是 PAR2 的一个关键药效团，可用于临床开发的优化。
