Abstract
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.
Highlights
Asthma is a heterogenous disease with multiple clinical phenotypes and newly described endotypes (Wenzel, 2012; Holgate et al, 2015), core features of airway constriction and hyper-responsiveness are likely common to multiple endotypes
The pharmacology of niclosamide and related compounds in providing potent but partial block of the iodide eYFP response yet full block of the TMEM16A chloride current appears most similar to the benchmark antagonists 1PBC and NTTP
While we describe the activity of seventeen niclosamide analogs, over 300 niclosamide analogs have been tested and the partial block of the iodide eYFP response is characteristic of this chemotype
Summary
Asthma is a heterogenous disease with multiple clinical phenotypes and newly described endotypes (Wenzel, 2012; Holgate et al, 2015), core features of airway constriction and hyper-responsiveness are likely common to multiple endotypes. Agonists of the β2-adrenergic receptor (β2AR) signal through the stimulatory G-protein, Gsα, to activate adenylate cyclase (AC), increase cAMP levels and activate PKA. While this mechanism offers the advantage of delivering a negative intracellular signal (cAMP/PKA) to airway smooth muscle (ASM) cells that blocks multiple contractants, repeated β-agonist use and poorly controlled inflammation can cause desensitization of this pathway. Proinflammatory cytokines or allergic inflammation has been found to increase expression of the inhibitory G-protein, Giα (Hakonarson et al, 1996), uncouple the β2AR from Gsα-induced activation of adenylate cyclase (Shore et al, 1997) and upregulate COX-2 and PGE2 production inducing heterologous β2AR desensitization of ASM cells and reduced β-agonist responsiveness (Moore et al, 2001)
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