Miner, Kent and Labitzke, Katja and Liu, Benxian and Wang, Paul and Henckels, Kathryn and Gaida, Kevin and Elliott, Robin and Chen, Jian Jeffrey and Liu, Longbin and Leith, Anh and Trueblood, Esther and Hensley, Kelly and Xia, Xing-Zhong and Homann, Oliver and Bennett, Brian and Fiorino, Mike and Whoriskey, John and Yu, Gang and Escobar, Sabine and Wong, Min and Born, Teresa L. and Budelsky, Alison and Comeau, Mike and Smith, Dirk and Phillips, Jonathan and Johnston, James A. and McGivern, Joseph G. and Weikl, Kerstin and Powers, David and Kunzelmann, Karl and Mohn, Deanna and Hochheimer, Andreas and Sullivan, John K. (2019) Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways. FRONTIERS IN PHARMACOLOGY, 10: 51. ISSN 1663-9812,
Full text not available from this repository. (Request a copy)Abstract
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-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 similar to 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 beta-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 beta-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED CHLORIDE CHANNEL; CA2+-ACTIVATED CL-CHANNEL; SMOOTH-MUSCLE-CELLS; ANOCTAMIN 1; ASTHMA PHENOTYPES; MUCIN SECRETION; ANIMAL-MODELS; EXPRESSION; CANCER; CURRENTS; TMEM16A antagonist; niclosamide; nitazoxanide; bronchodilator; desensitization; airway smooth muscle (ASM); calcium-activated chloride channel; drug repositioning |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Apr 2020 11:18 |
| Last Modified: | 21 Apr 2020 11:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27545 |
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