AUTHOR=Miner Kent , Labitzke Katja , Liu Benxian , Wang Paul , Henckels Kathryn , Gaida Kevin , Elliott Robin , Chen Jian Jeffrey , Liu Longbin , Leith Anh , Trueblood Esther , Hensley Kelly , Xia Xing-Zhong , Homann Oliver , Bennett Brian , Fiorino Mike , Whoriskey John , Yu Gang , Escobar Sabine , Wong Min , Born Teresa L. , Budelsky Alison , Comeau Mike , Smith Dirk , Phillips Jonathan , Johnston James A. , McGivern Joseph G. , Weikl Kerstin , Powers David , Kunzelmann Karl , Mohn Deanna , Hochheimer Andreas , Sullivan John K. TITLE=Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways JOURNAL=Frontiers in Pharmacology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00051 DOI=10.3389/fphar.2019.00051 ISSN=1663-9812 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.