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Front Pharmacol. 2019 Feb 14;10:51. doi: 10.3389/fphar.2019.00051. eCollection 2019.

Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways.

Author information

1
Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA, United States.
2
Department of Therapeutic Discovery, Amgen Inc., Regensburg, Germany.
3
Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, United States.
4
Department of Medicinal Chemistry, Amgen Inc., Thousand Oaks, CA, United States.
5
Department of Inflammation Research, Amgen Inc., Seattle, WA, United States.
6
Department of Comparative Biology and Safety Sciences, Amgen Inc., Seattle, WA, United States.
7
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, United States.
8
Department of Comparative Biology and Safety Sciences, Amgen Inc., South San Francisco, CA, United States.
9
Genome Analysis Unit, Amgen Inc., South San Francisco, CA, United States.
10
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.

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.

KEYWORDS:

TMEM16A antagonist; airway smooth muscle (ASM); bronchodilator; calcium-activated chloride channel; desensitization; drug repositioning; niclosamide; nitazoxanide

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