RT Journal Article
SR Electronic
T1 Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 254888
DO 10.1101/254888
A1 Kent Miner
A1 Katja Labitzke
A1 Benxian Liu
A1 Paul Wang
A1 Kathryn Henckels
A1 Kevin Gaida
A1 Robin Elliott
A1 Jian Jeffrey Chen
A1 Longbin Liu
A1 Anh Leith
A1 Esther Trueblood
A1 Kelly Hensley
A1 Xing-Zhong Xia
A1 Oliver Homann
A1 Brian Bennett
A1 Mike Fiorino
A1 John Whoriskey
A1 Gang Yu
A1 Sabine Escobar
A1 Min Wong
A1 Teresa L. Born
A1 Alison Budelsky
A1 Mike Comeau
A1 Dirk Smith
A1 Jonathan Phillips
A1 James A. Johnston
A1 Joe McGivern
A1 Kerstin Weikl
A1 David Powers
A1 Karl Kunzelmann
A1 Deanna Mohn
A1 Andreas Hochheimer
A1 John K. Sullivan
YR 2018
UL http://biorxiv.org/content/early/2018/11/14/254888.abstract
AB 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.