Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways
Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways
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DOI：
10.3389/fphar.2019.00051
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发表时间：
2019-02-14
影响因子：
5.6
通讯作者：
Sullivan, John K.
中科院分区：
文献类型：
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作者：
Miner, Kent;Labitzke, Katja;Sullivan, John K.
严重哮喘的需求尚未得到满足，其中大约 40% 的患者表现出较差的 β 受体激动剂反应性，每天都会出现症状并频繁恶化。 Ca2+ 激活的 Cl- 通道拮抗剂 TMEM16A 提供了一种新机制，可扩张支气管气道并阻断严重疾病中的多重收缩。为了鉴定 TMEM16A 拮抗剂，我们筛选了包含大约 580,000 种化合物的库。驱虫药氯硝柳胺、硝唑尼特和相关化合物被确定为有效的 TMEM16A 拮抗剂，可阻止气道平滑肌去极化和收缩。为了评估 TMEM16A 拮抗剂是否抵抗限制 β 激动剂作用的使用和炎症脱敏途径，我们使用最大收缩气道或用细胞因子混合物预处理的气道在恶劣条件下测试了它们的功效。令人惊讶的是，TMEM16A 拮抗剂可完全扩张支气管气道，而 β-激动剂异丙肾上腺素仅显示出部分效果。因此，TMEM16A 拮抗剂以及氯硝柳胺和硝唑尼特的重新定位代表了对现有疗法控制不佳的严重哮喘和 COPD 患者的重要额外治疗。值得注意的是，药物再利用也引起了人们对氯硝柳胺和硝唑尼特作为癌症和传染病新疗法的广泛兴趣。我们首次将 TMEM16A 确定为这些药物的分子靶标，从而为它们治疗除呼吸系统疾病之外的这些疾病的机制提供了新的见解。
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.