Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways

Miner, Kent; Labitzke, Katja; Liu, Benxian; Wang, Paul; Henckels, Kathryn; Gaida, Kevin; Elliott, Robin; Chen, Jian Jeffrey; Liu, Longbin; Leith, Anh; Trueblood, Esther S.; Hensley, Kelly; Xia, Xing-Zhong; Homann, Oliver; Bennett, Brian D.; Fiorino, Mike; Whoriskey, John; Yu, Gang; Escobar, Sabine; Wong, Min‐Liang; Born, Teresa L.; Budelsky, Alison; Comeau, Mike; Smith, Dirk E.; Phillips, Jonathan E.; Johnston, James A.; McGivern, J.; Weikl, Kerstin; Powers, David; Kunzelmann, Karl; Mohn, Deanna; Hochheimer, Andreas; Sullivan, John K.

doi:10.1101/254888

Cited by 27 publications

(39 citation statements)

References 84 publications

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“…5 and 6). Although both substances potently inhibit TMEM16A 12,13 , they are not specific to TMEM16A. Benzbromarone is primarily known as an uricosuric compound and niclosamide is used for the treatment of tapeworm infestations.…”

Section: Discussionmentioning

confidence: 99%

“…The present data indicate an essential contribution of TMEM16A to the development of PKD. Recent studies identified two FDA-approved drugs, niclosamide and benzbromarone, as potent inhibitors of TMEM16A 12,13 . We therefore examined if treatment with niclosamide and benzbromarone in vivo will inhibit enlargement of renal cysts in Pkd1 −/− animals.…”

Section: Knockdown Of Pkd1 Causes Upregulation Of Tubular Expressionmentioning

confidence: 99%

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Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

et al. 2020

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In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl − secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca 2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca 2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.

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Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of Pkd1 Causes Upregulation Of Tubular Expressionmentioning

confidence: 99%

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

et al. 2020

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“…There is a paucity of published pharmacokinetic data for niclosamide and this prohibited a thorough investigation of exposures in relation to activity over its entire dosing interval. Both nitazoxanide and niclosamide have also been reported to be potent antagonists of TMEM16A, calcium activated chloride channels that modulate bronchodilation [57].…”

Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

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“…In peripheral blood mononuclear cells exposed to influenza virus, nitazoxanide potentiated the release of INF-α and INF-β by fibroblasts [ 135 ]. In addition, nitazoxanide appears also to act as a bronchodilator in testing models by blocking the calcium-activated chloride channel TMEM16A [ 141 ].…”

Section: Miscellaneous Antiviral Agentsmentioning

confidence: 99%

Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

Al‐Horani

Kar

2020

Viruses

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The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.

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Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways

Cited by 27 publications

References 84 publications

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

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