TOPIC

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airway

Author(s)

Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, Karl Kunzelmann, Deanna Mohn, Andreas Hochheimer, John K. Sullivan

Year

2018

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.

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