Niclosamide-A promising treatment for COVID-19.

JC devised the idea for the article. SS performed the initial literature search. SS, MF, JG, SK and JG wrote the first draft. AW designed Figure  1 , IL designed Figure  2 and SS, AW, JG and JC designed Figure  3 . SS, AW, JG, MS, RS and JC critically revised the article. All authors approved the final version.

Structurally, niclosamide (Figure  1 ) belongs to a large group of lipophilic, weakly acidic molecules called salicylanilides, a derivative of salicylic acid (Pearson & Hewlett,  1985 ). Niclosamide is listed on the WHO's list of essential medications and chewable tablets have been approved for use as an anti‐helminthic agent for cestode (tapeworm) infections for over 40 years with a daily oral dose of 2 g niclosamide (Andrews et al.,  1982 ). Niclosamide inhibits oxidative phosphorylation and stimulates ATP activity in the mitochondria of cestodes, killing both the scolex and the proximal segments of the tapeworm (Al‐Hadiya,  2005 ; Weinbach & Garbus,  1969 ). It has been shown to affect several signal transduction pathways such as Wnt/ β‐catenin , mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), signal transducer and activator of transcription 3 (STAT3 ), nuclear factor kappa‐light‐chain‐enhancer of activated B cells (nuclear factor‐κB; NF‐κB) and Notch pathways, all indicating its potential to treat conditions such as cancer (summarized in Table  1 ), chronic medical diseases, and bacterial and viral infections. The chemical structure of niclosamide, C 13 H 8 Cl 2 N 2 O 4 Mechanism of action of niclosamide in various cancers Abbreviations: Bcl, B‐cell lymphoma; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; EMT, epithelial to mesenchymal transition; ERK, extracellular signal‐regulated protein kinase; HCC, hepatocellular carcinoma; LC3, microtubule‐associated protein 1A/1B‐light chain 3; LEF, lymphoid enhancer factor; MAP, mitogen‐activated protein; MCL‐1, myeloid cell leukaemia sequence 1; MEK, mitogen‐activated protein kinase kinase; MMP, matrix metallopeptidase; mTOR, mechanistic target of rapamycin; NFAT, nuclear factor of activated T cells; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PD‐L1, programmed death‐ligand 1; PI3K, phosphoinositide 3‐kinases; ROCK, rho‐associated coiled‐coil kinase; STAT3, signal transducer and activator of transcription 3; TCF, T‐cell factor; VEGF, vascular endothelial growth factor. Oral niclosamide is only partially absorbed from the intestinal tract with a low bioavailability of 5.5%–10% and is rapidly eliminated by the kidneys with no cumulative toxic effects (Andrews et al.,  1982 ). Distribution studies in rodents with oral doses of 40 mg·kg −1 niclosamide ethanolamine (i.e. ~34 mg·kg −1 niclosamide) and 50 mg·kg −1 niclosamide demonstrate that tissue levels are highest in excretory organs (intestines, liver and kidney) and low to negligible levels are achieved in other tissues (such as the brain, heart and lungs) (Duhm et al.,  1961 ; Tao et al.,  2014 ). Oral administration of niclosamide in rodents reached a mean maximum plasma concentration ( C max ) of 22.4 ng·ml −1 (1 mg·kg −1 ), 354 ng·ml −1 (5 mg·kg −1 ) and 644 ng·ml −1 (~34 mg·kg −1 ) (Chang et al.,  2006 ; Choi et al.,  2021 ; Tao et al.,  2014 ). In humans receiving niclosamide (2 g·day −1 , p.o.), the median C max ranged from 665 to 759 ng·ml −1 in five colorectal cancer patients and from 250 to 6000 ng·ml −1 in healthy subjects (Andrews et al.,  1982 ; Burock, Daum, Keilholz, et al.,  2018 ). In three prostate cancer patients receiving 1.5 g·day −1 , p.o., the C max ranged from 35.7 to 182 ng·ml −1 , respectively (Schweizer et al.,  2018a , 2018b ). Therapeutic plasma levels in rodent studies (using doses from 5 mg·kg −1 ·day −1 , p.o., to 200 mg·kg −1 ·day −1 , p.o.) likely exceed the plasma levels in humans prescribed a 2 g p.o. dose, based on the results from Tao et al. ( 2014 ) and assuming dose linearity. This therefore raises additional pharmacokinetic (PK) and pharmacodynamic (PD) challenges as well as potential toxicity issues for human clinical trials.

Based on promising preclinical data, niclosamide is currently being evaluated as a potential COVID‐19 treatment in 18 human clinical trials relying on different formulations and/or routes of administration. Details of these trials can be found on public registries such as ClinicalTrials.gov and the WHO's Trial search website. Twelve of these trials are in Phase 2/3 and investigate the efficacy of niclosamide across the full COVID‐19 disease spectrum (Figure  3 and Table  2 ). COVID‐19 clinical trials investigating niclosamide. Study references refer to National ClinicalTrials.gov (NCT), Clinical Trials Registry – India (CTRI) or EU Clinical Trials Register (EUCTR), where applicable, are included in Table  2 . The majority of studies are dual listed on the WHO International Clinical Trials Registry Platform (ICTRP). Study NCT04372082 was terminated prior to randomization and is therefore excluded from the figure COVID‐19 clinical trials utilizing niclosamide NCT04592835 Phase 1 to assess safety, tolerability and PK NCT04524052 Phase 1 to assess safety, tolerability and PK/PD NCT04749173 Phase 1 to assess safety, tolerability and PK NCT04541485 Phase 1 to assess safety, tolerability and PD NCT04576312 Phase 1 NCT04644705 Phase 1 to assess safety and PK NCT04750759 EUCTR2020‐002233‐15‐DE Phase 2 NCT04932915 EUCTR2021‐001036‐25‐DE Phase 2 study to assess safety and efficacy NCT04753619 Phase 2 open‐label randomized controlled trial NCT04399356 Phase 2 NCT04858425 Phase 2 NCT04436458 Phase 2 NCT04542434 Phase 2 CTRI/2020/04/024949 Phase 2 CTRI/2021/05/033791 Phase 2 NCT04870333 EUCTR2020‐004144‐28‐GB Phase 2/3 Chemoprophylaxis trial in vulnerable patients NCT04603924 Phase 2/3 TACTIC‐E/ NCT04393246 Phase 2/3 NCT04558021 Phase 3 NCT04372082 Phase 3 NCT05087381 Phase 4 Note : Study references refer to National ClinicalTrials.gov (NCT), Clinical Trials Registry – India (CTRI) or EU Clinical Trials Register (EUCTR). The majority of studies are dual listed on the WHO International Clinical Trials Registry Platform (ICTRP). A similar trial set‐up in the Philippines was terminated (9 December 2020) due to a lack of COVID‐19 patients ( NCT04541485 ). Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics; SoC, standard of care. In the pre‐symptomatic and mild COVID‐19 disease stage, the potent antiviral activity of niclosamide is thought to limit disease symptomatology and progression. However, as COVID‐19 progresses towards moderate and severe disease, the bronchodilatory and anti‐inflammatory effects of niclosamide might contribute to efficacy. Its antibacterial efficacy could also benefit COVID‐19 patients at risk for secondary bacterial infections, which is one of the leading causes of mortality in COVID‐19 (Cevik et al.,  2020 ), particularly since the introduction of immunomodulators such as dexamethasone and tocilizumab as standard of care (SoC) medications. Of the 14 Phase 2/3 trials (Table  2 ), 11 trials are investigating oral formulations of niclosamide with seven using the marketed oral tablet form of niclosamide (also known under the tradename Yomesan), one utilizing capsules and one a novel suspension. However, one of these is registered as terminated due to subtherapeutic plasma levels and another one was withdrawn due to evidence showing the non‐effectiveness of hydroxychloroquine , which was being tested in one of the study arms. Niclosamide in a chewable tablet form is being investigated in moderate COVID‐19 patients with gastrointestinal signs and symptoms at a dose of 400 mg three times per day for 14 days ( National ClinicalTrials.gov (NCT) number 04542434, NCT04858425 ). Mortality, adverse event rate, faecal virus clearance and several clinical features are listed as outcome measures. Niclosamide in a chewable tablet form is also being investigated (in addition to standard of care(SoC) in asymptomatic/mild outpatient cases at 500 mg two times per day for 7–14 days (Clinical Trials Registry – India (CTRI)/2020/04/024949), mild–moderate cases at 2 g four times per day for 7 days ( NCT04399356 ), moderate COVID‐19 subjects at 2 g·day −1 for 7 days (Clinical Trials Registry – India/2021/05/033791), moderately ill hospitalized COVID‐19 cases with gastrointestinal symptoms ( NCT04436458 ) and mild–severe patients receiving a 2 g loading dose + 1 g every 12 h on Day 1 and then 1 g three times per day for 7 days ( NCT04753619 ). The last trial was recently published (Abdulamir et al.,  2021 ). This randomized, open‐label, controlled trial included 75 mild–severe COVID‐19 patients treated with SoC plus niclosamide (tablet) orally versus 75 patients receiving SoC only. Each group consisted of 25 mild, 25 moderate and 25 severe cases (defined according to WHO classification criteria). In moderate and severe, but not mild COVID‐19, patients receiving ‘niclosamide + SoC’ had a significantly shorter time to recovery, especially in patients with comorbidities compared with SoC only. Survival was not significantly increased. The small sample size in each disease severity group and the open‐label nature of the study have limited any robust conclusions being drawn from the study. A niclosamide suspension is currently being tested in moderate hospitalized COVID‐19 patients receiving 200 mg (10 ml) niclosamide three times per day for 5 days (in addition to SoC), with time from admission to clinical recovery as the primary outcome measure. Another trial utilizes four 250 mg niclosamide capsules two times per day for seven consecutive days in moderate–severe cases defining safety and median time to hospital discharge as the primary outcome measures. Efficacy readouts of the other clinical trials investigating oral niclosamide preparations across the full COVID‐19 disease spectra are awaited. To address concerns around poor oral bioavailability of niclosamide, a formulation administered via the intramuscular route was developed. It is currently being investigated in healthy volunteers to assess its safety, tolerability and pharmacokinetics/pharmacodynamics (PK/PD) in 40 COVID‐19 patients (Table  2 ). This trial is a multiple‐dose ascending study injecting different volumes of a 24% suspension at four predefined injection sites. Incidence of treatment‐emergent adverse events and time to and rate of eradication of SARS‐CoV‐2 are the primary and secondary endpoints, respectively. Notably, Choi et al. ( 2021 ) performed a pharmacokinetics study in rats comparing equal doses of niclosamide administered via the intramuscular, intravenous and oral routes. They found increased systemic exposure with the intramuscular injection with a 70‐fold higher C max and 13‐fold higher area under the curve (AUC) compared with the oral route. The intramuscular bioavailability was found to be 65% compared with 5.5% via the oral route, highlighting the substantial improvement via the intramuscular route. In another approach, the poor oral availability of niclosamide has been circumvented by developing a formulation optimized for inhalation and intranasal administration, aiming to achieve a high concentration in the lung (as the target tissue) whilst limiting systemic exposure to diminish side effects. Backer et al. ( 2021 ) published a randomized, double‐blind, placebo‐controlled Phase 1 trial assessing the safety and pharmacokinetics following inhaled (nebulized) and intranasal administration of a new formulation of niclosamide in healthy volunteers. Participants were randomly assigned to ascending single doses and five repetitive doses over 2.5 days. Inclusion criteria included a forced expiratory volume in 1 s (FEV1) of 80%. The study did not record any serious adverse events except mild irritation of the upper airways, increased fractional exhaled nitric oxide (FeNO) in 14.7% and an asymptomatic drop in forced expiratory volume in 1 s in 11.8% of subjects. A limitation of the study, however, was the exclusion of patients with underlying respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD), thus excluding patients who would be at the highest risk for adverse events via the inhalational route. The mean C max of niclosamide following the highest dose of 52.9 mg was 337 ng·ml −1 (two times per day, repeat dosing) and 424 ng·ml −1 (single dose). This is lower compared with plasma levels of the (much higher) 2 g, p.o., dose used in anti‐helminthic treatment (Andrews et al.,  1982 ; Burock, Daum, Keilholz, et al.,  2018 ; Schweizer et al.,  2018a , 2018b ). The lower C max would potentially limit the systemic side effects seen with oral dosing, a route that has been in use since the 1960s. Following this Phase 1 study, three Phase 2/3 clinical trials were initiated, two of which are investigating the efficacy of the intranasal administration only—PROTECT‐V trial (PROphylaxis for paTiEnts at risk of COVID‐19 infecTion), overseen by the NIHR Covid‐19 Understanding and Elimination‐Trials Implementation Panel (CUE‐TIP) is a pre‐exposure prophylaxis trial in 1500 vulnerable renal patients who receive 140 μl of a 1% niclosamide ethanolamine solution (equivalent to 1.4 mg of niclosamide ethanolamine salt) in each nostril two times per day for up to 9 months, and PREVENT trial (asymptomatic/mild COVID‐19 patients receiving UNI91103 two times per day for 10 days). Finally, the TACTIC‐E trial (mulTi‐Arm therapeutiC sTudy in pre‐Icu patients admitted with COVID‐19—Experimental drugs) utilizes a combination of intranasal and nebulized niclosamide in moderate to severe COVID‐19 (Fisk et al.,  2021 ; Lu et al.,  2020 ; TACTIC‐E Trial,  2020 ). For the latter, combined intranasal and intra‐pulmonary (via the nebulized route) administration of niclosamide has the potential to be an efficacious approach as aerosol application of niclosamide via the inhaled and intranasal routes enables local delivery at the site of disease. Using this local delivery approach, niclosamide levels in target tissues are expected to be higher than plasma levels (Backer et al.,  2021 ; UNION therapeutics,  2020 ) and achieve therapeutic concentrations at the primary site of infection. The targeted nasal administration is crucial because the nasopharynx and nasal cavity are both an entry point and a reservoir for SARS‐CoV‐2 (Gallo et al.,  2021 ; Sungnak et al.,  2020 ). Overall, the breadth and spectrum of clinical trials utilizing niclosamide across the different disease stages of COVID‐19 will provide valuable human clinical and pharmacological data and have the potential to enable the development of niclosamide as an effective anti‐COVID‐19 agent, either in its own right or an as adjunct.

Evidence has accumulated that niclosamide is a multi‐functional drug that can modulate several signalling pathways and biological processes. It has shown preclinical activity in many disease models, from cancer and metabolic diseases to various infections. The leading causes of mortality in COVID‐19 patients are an exaggerated immune response, as well as secondary bacterial infections and the development of acute respiratory distress syndrome. Niclosamide can function both as an anti‐bacteriostatic agent and as an immunomodulator; thus, it has unique advantages over other agents currently being tested in the COVID‐19 arena. More importantly, niclosamide broad‐spectrum antiviral properties and potent inhibition of SARS‐CoV‐2 mean it can be developed rapidly as a cost‐effective therapeutic approach against COVID‐19 and hold the promise of widespread utilization as a primary or adjunctive agent. Niclosamide use could be further extended to other viral respiratory infections with a high unmet medical need, such as rhinovirus, influenza virus and respiratory syncytial virus. The reformulation of niclosamide into a nebulized and nasal route has the potential to provide the drug at therapeutic concentrations to the site of viral replication and disease and thereby minimize systemic toxicity. We anticipate that the results of the upcoming clinical trials of niclosamide in COVID‐19 will prove to be an important milestone in managing the pandemic globally. Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander, Christopoulos, Davenport, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Pawson, Southan, Davies, et al.,  2021 ; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Pawson, Southan, Davies, Beuve, et al.,  2021a ; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Pawson, Southan, Davies, Boison, et al.,  2021b ).

The favourable safety profile of niclosamide in treating humans with tapeworm infection could be due to the fact that the organ of interest was the gut and the drug did not need to be absorbed systemically and therefore did not get the chance to negatively modulate systemic signalling cascades. Systemic delivery is required for infections, cancers and metabolic diseases that have shown to be responsive to niclosamide. The safety profile of niclosamide in these conditions is largely unexplored and future studies are required for a clearer picture of its toxicity. The oral dose of niclosamide as a cestocidal agent is 2 g as a single dose, and this leads to a wide range of serum concentrations as described above (Andrews et al.,  1982 ), mainly due to variable absorption rates. The combination of a low oral bioavailability and a wide range of serum concentrations results in unpredictable efficacy in clinical studies. Additional studies with a formulation that gives high bioavailability are required before niclosamide can be used more widely. One of the obstacles in this direction is that a direct target of niclosamide remains undiscovered. There is great interest in conducting studies to elucidate the structure–activity relationship of niclosamide and thereby to identify novel derivatives of niclosamide that might have better bioavailability (H. Chen et al.,  2013 ). A recent study that combined structure‐assisted drug design identified a mechanism‐based inhibitor (N3) and then determined the crystal structure of M pro (main protease of SARS‐CoV‐2) in complex with this inhibitor (Z. Jin et al.,  2020 ). Through a combination of structure‐based virtual and high‐throughput screening, the investigators assayed more than 10,000 compounds as inhibitors of M pro and demonstrated that a robust screening strategy can rapidly discover drugs for new infections. Although these crystal structures provide useful new insights into drug discovery, extensive efforts are still needed to identify effective binding pockets for small molecules such as niclosamide and thereby validate the drug targets. The challenges involved in repurposing niclosamide begin with its stable crystalline structure and its lipophilicity that restrict its solubility in water. This resulted in high oral doses in preclinical trials and therefore raised safety concerns for clinical trials as it made therapeutically relevant concentrations of the drug difficult to achieve. For example, in a Phase 1 dose‐escalation study testing oral niclosamide plus standard dose enzalutamide for prostate cancer, subjects on the higher dose (1000 mg three times per day) experienced dose‐limiting toxicities related to the gastrointestinal tract (colitis, diarrhoea, nausea and vomiting) resulting in the treatment being discontinued. However, plasma concentrations at the maximum tolerated dose (500 mg three times per day) were not consistently above the expected therapeutic threshold (Schweizer et al.,  2018a , 2018b ). The adverse events relating to the two patients who discontinued treatment (in the 1000 mg three times per day group) were most likely driven by the high local niclosamide concentrations in the gastrointestinal tract rather than the high systemic exposure. Peak plasma levels for the 1000 mg three times per day dose ( C max  = 149–182 ng·ml −1 , AUC 0 −  t  = 629–676 ng·h −1 ·ml −1 [min–max]) were below or similar to the plasma levels of studies using a 1.5 or 2 g daily dose, which is well tolerated (Burock, Daum, Tröger, et al.,  2018 ). Of note, the COVID‐19 trials with niclosamide are using the approved 2 g p.o. daily dose (or lower inhalation/intranasal and intramuscular doses), and therefore, one would expect even smaller proportions of the drug to reach the gastrointestinal tract. Improvement in pharmacological and pharmacokinetics properties through reformulation can help overcome some hurdles and make use of the drug more mainstream. In a Phase Ib prostate cancer trial, a novel reformulated orally bioavailable niclosamide/PDMX1001 (1200 mg three times per day) achieved plasma levels exceeding the therapeutic threshold ( C max  = 70–236 ng·ml −1 and pre‐dose trough concentration (C trough )= 100–212 ng·ml −1 [min–max] vs. target dose of 32 ng·ml −1 ) when combined with abiraterone and prednisolone and was well tolerated with no dose‐limiting toxicities (Parikh et al.,  2021 ). Zeyada et al. ( 2020 ) employed a novel oral niclosamide pluronic‐based nanoformulation and tested its effect in hepatocellular carcinoma in rats (70 mg·kg −1 6 days·week −1 for 3 weeks, p.o.). These nanoparticles had sustained release properties up to 7 days and restored liver integrity, reduced alpha‐fetoprotein (AFP) levels and showed better anticancer activities compared with the drug alone. Furthermore, the trials described above using intramuscular injection or novel formulations of oral niclosamide in COVID‐19 will further elucidate its safety and efficacy, driven by systemic exposures. Direct delivery of the drug into the respiratory and nasal routes could overcome some such hurdles and generate high drug concentrations at the site of primary infection in COVID‐19 infection, primarily the nasal cavity and lung tissue. Furthermore, this approach is thought to limit systemic exposure and hence decrease the risk of systemic side effects.

Given niclosamide potent antiviral activity within the beta‐CoV family, it became apparent that it could be a potent antiviral against SARS‐CoV‐2. A study by Jeon et al. ( 2020 ) testing 3000 FDA‐approved drugs and other well‐characterized molecules identified niclosamide as the most potent inhibitor of SARS‐CoV‐2 in Vero cells, with a 40‐fold higher potency than remdesivir. Furthermore, Weiss et al. ( 2021 ) showed that niclosamide potency is conserved against the Alpha, Beta and Delta SARS‐CoV‐2 variant in Vero transmembrane serine protease 2 (TMPRSS2) cells and validated niclosamide strong antiviral activity in a human airway epithelial model. Niclosamide has also been shown to inhibit SARS‐CoV‐2 in vivo . Specifically, an inhaled niclosamide formulation was developed and tested in a murine infection model of SARS‐CoV‐2 (Brunaugh et al.,  2021 ). Administration of niclosamide (0.24 mg·kg −1 ·day −1 , intranasal) to SARS‐CoV‐2‐infected mice for 10 days improved survival and significantly reduced viral loads. Niclosamide further exhibited potent properties as an anti‐MRSA bacteriostatic agent and modulated various inflammatory cytokines such as IL‐1β, IL‐6 and TNF‐α. These findings suggest that niclosamide could also address secondary bacterial infections, which is one of the leading causes of death in COVID‐19 patients. It is evident that local administration in these viral infection models allowed substantially lower doses (0.25 and 5 mg·kg −1 ) compared with oral doses, thereby increasing the therapeutic window in terms of safety issues arising from excessive systemic exposure from oral dosing. The antiviral activity of niclosamide against SARS‐CoV‐2 is complex and involves multiple cellular processes as illustrated in Figure  2 . SARS‐CoV‐2 uses the angiotensin‐converting enzyme 2 (ACE2 ) as a cellular entry receptor in permissive cells of the respiratory tract and the spike proteins initiate the merging of the viral envelope with the host cell cytomembrane (Zhou et al.,  2020 ). Following receptor binding and conformational changes in the spike protein, cathepsin L mediates proteolysis within endosomes leading to viral entry into host cells, as it has been shown for SARS‐CoV (Gomes et al.,  2020 ; Huang et al.,  2006 ; Simmons et al.,  2005 ). The protonophoric activity of niclosamide that causes endosomal neutralization is thought to interfere with viral entry and egress preventing SARS‐CoV‐2 genome release and maturation. This mechanism has been derived from studies with pH‐dependent respiratory viruses—rhinovirus and influenza virus—which also use pH‐sensitive mechanisms of the endosomal pathway for viral entry and egress, similar to SARS‐CoV‐2 (Jurgeit et al.,  2012 ). Garrett et al. ( 2021 ) recently demonstrated that the total lipid profile is amplified during SARS‐CoV‐2 infection in VeroE6 cells and treatment with niclosamide led to a reduction in lipids available for virus production. Additionally, in primary human lung cells and intestinal organoids, niclosamide enhances autophagy through inhibition of S‐phase kinase‐associated protein 2 thus further attenuating SARS‐CoV‐2 replication (Gassen et al.,  2021 ). Potential mechanisms of antiviral activity have been illustrated in this figure. These include (i) endosomal pH neutralization to prevent viral replication, (ii) promotion of autophagy via inhibition of S‐phase kinase‐associated protein 2 (SKP2), (iii) decreased mucus plugging via inhibition of TMEM16A (calcium activated chloride channel; CaCC) and (iv) prevention of syncytia formation by ion channel inhibition. Abbreviation: BCN1, beclin‐1; ATG14, autophagy related 14; SARS‐COV‐2, severe acute respiratory syndrome coronavirus‐2. Created with BioRender.com Syncytia formation in SARS‐CoV‐2‐infected pneumocytes has been observed in COVID‐19 lungs. To identify inhibitors of spike‐driven syncytia formation, a high‐content microscopy‐based screening of more than 3000 compounds was conducted (L. Braga et al.,  2021 ). The screen identified efficacious drugs that inhibited viral replication, with one of the most potent being niclosamide. Niclosamide also has potent bronchodilatory effects, inhibits excessive mucus production and down‐regulates the release of pro‐inflammatory cytokines such as IL‐8 by inhibiting TMEM16A (Cabrita et al.,  2019 ). Due to its effects on intracellular calcium levels, niclosamide can inhibit other cytokines and could therefore play an important role in controlling the cytokine storm and acute respiratory distress syndrome (ARDS) in acutely ill COVID‐19 patients. The above studies show several plausible mechanisms of action of niclosamide against COVID‐19, including prevention of viral entry, prevention of viral replication via autophagy inhibition and, finally, inhibition of spike‐driven syncytia formation. Importantly, unlike vaccines or monoclonal antibodies, the host‐directed mechanism of action of niclosamide means its antiviral efficacy is less likely to be affected by the emergence of SARS‐CoV‐2 variants, as has been shown for the Alpha, Beta and Delta variant by Weiss et al. ( 2021 ). In conclusion, these studies have confirmed potent, multi‐faceted and pleiotropic activity of niclosamide against SARS‐CoV‐2, targeting multiple aspects of the viral life cycle.

Drug repurposing has emerged as an attractive alternative to the conventional approach of drug discovery, which is often exhaustive and arduous (Ashburn & Thor,  2004 ). It is a process of identifying new therapeutic roles for a drug that has already been established for the treatment of another condition. The discovery of a new drug and its journey to the market is a process fraught with risks involving toxicity and lack of efficacy, costing billions of dollars and requiring a long timeline. Repurposing therefore offers several advantages over de novo drug development, such as reduced development timelines, reduced costs and substantially lower risks, as the safety and pharmacokinetic profile of the drug is already established (S. Pushpakom et al.,  2019 ). The risk of failure is lower because the repurposed drug has been shown to be safe in preclinical models and humans, provided early‐stage trials have been completed. As a result, the timeframe for drug development is significantly shorter (Breckenridge & Jacob,  2019 ). Historically, drug repurposing has been mostly serendipitous, usually after a drug was found to have a newly recognized off‐target effect (Nosengo,  2016 ). Well‐known examples are the use of minoxidil for hair loss, sildenafil for erectile dysfunction and thalidomide for multiple myeloma (Pushpakom et al.,  2019 ). However, recent successes have encouraged the development of more systematic approaches resulting in the identification of a number of promising candidate drugs (Hurle et al.,  2013 ). In more recent years, drug repurposing screens have emerged as an attractive strategy to respond swiftly to emerging infectious diseases (Ashburn & Thor,  2004 ). Food and Drug Administration (FDA; U.S.A.)‐approved drugs that can achieve a modest antimicrobial activity are a safe and increasingly popular response mechanism to emerging infections. The drugs concerned can be made immediately available for use in clinical trials as they have known safety profiles at the licensed doses and this has had a huge impact during the COVID‐19 pandemic. For example, dexamethasone was repurposed in the RECOVERY trial (Horby et al.,  2021 ) and is estimated to have saved 1 million lives globally by March 2021 (NHS England,  2021 ) whereas tocilizumab, a repurposed drug for moderate to severe rheumatoid arthritis, is licensed for treating hospitalized patients with moderate to severe COVID‐19 (Gordon et al.,  2021 ; RECOVERY Collaborative Group,  2021 ). The CORONA Project (a joint initiative by the Castleman Disease Collaborative Network and the Centre for Cytokine Storm Treatment & Laboratory) is tracking all other novel and repurposed drugs for COVID‐19 and assigns the drugs a ‘grade’, based on treatment efficacy and whether pre‐specified endpoints are met (Venkatesan,  2021 ). Here, we review the preclinical models that have demonstrated the pluripotential effects of niclosamide as well as some limited human data in a variety of disease states that suggest it could be an agent of choice in COVID‐19.

The outbreak of coronavirus disease 2019 (COVID‐19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. A rapid rise in the numbers of COVID‐19 cases followed (Paules et al.,  2020 ) and as of January 2022, there have been over 296 million cases of COVID‐19 and 5.5 million deaths (WHO,  2022 ). Healthcare systems have been globally overwhelmed (Miller et al.,  2020 ) and projection studies predict that rapid transmission dynamics will potentially be at play well into 2025 (Kissler et al.,  2020 ). Viral vector and mRNA vaccines have proved an overwhelming success in controlling the pandemic (Rotshild et al.,  2021 ) and as of January 2022, nearly 9 billion vaccine doses have been administered (WHO,  2022 ). However, vaccines alone are unlikely to be sufficient in vulnerable patient populations (i.e. elderly, cancer, primary immune deficiencies, transplant recipients or dialysis) and patients who receive concurrent medical treatments that supress the immune system may not mount a satisfactory antibody response. Additionally, global herd immunity is unlikely to be achieved due to the constant evolution of new variants of concern and waning of natural or stimulated antibody responses over time. Geopolitical logistics and vaccine nationalism also make it unlikely that these vaccines will be equitably available across the globe for a few more years. Therefore, parallel strategies such as effective novel therapeutic interventions must be rapidly developed. Intensive and collaborative research efforts have resulted in a number of treatment options for COVID‐19. The antivirals, remdesivir (Beigel et al.,  2020 ) and molnupiravir (Jayk Bernal et al.,  2021 ), neutralizing monoclonal antibodies, casirivimab , imdevimab (Somersan‐Karakaya et al.,  2021 ) and sotrovimab (Gupta et al.,  2021 ), IL‐6 antibodies, tocilizumab (Gordon et al.,  2021 ; RECOVERY Collaborative Group,  2021 ) and dexamethasone (Horby et al.,  2021 ) are the primary treatment options currently approved for COVID‐19, but they can result in serious systemic adverse effects and only moderately affect the clinical outcomes. The limitations of these therapies highlight the need for ongoing development of life‐saving medications to help fight the virus. Coronaviruses (CoVs) are large, enveloped, positive sense and single‐stranded RNA viruses belonging to the family Coronaviridae within the order Nidovirales (Y. Chen et al.,  2020 ). They can infect several mammalian hosts and are divided into four genera: ‐ Alpha, Beta, Gamma and Delta, of which Alpha and Beta CoVs are known to infect humans. Full‐genome sequencing and phylogenetic analyses have indicated that the CoV that causes COVID‐19 was in the same subgenus as the SARS virus (Fehr & Perlman,  2015 ) and was named on the basis of its appearance under electron microscopy. Human CoV infections usually cause mild, self‐limiting respiratory infection. However, the epidemics of SARS‐CoV and Middle East respiratory syndrome coronaviruses (MERS‐CoV) caused alarming morbidity and mortality in 2002–2003 and 2012, respectively (Gao et al.,  2016 ), and COVID‐19 has underscored the continued risk of pandemics caused by such viruses. Risk factors for severe COVID‐19 across the globe include old age, race, gender, obesity, cardiovascular disease, diabetes, chronic lung disease and immunosuppression. Therefore, drugs that target pleiotropic mechanisms may be important. CoVs have a large genome and a higher mutation rate compared with other RNA viruses, hence eradicating them definitively is difficult (Gralinski & Baric,  2015 ). Broad‐spectrum inhibitors of emerging CoVs are therefore needed and repurposing existing drugs has been validated as a means to tackle the SARS‐CoV‐2 pandemic, as well as enabling future pandemic preparedness.

JC and RS acknowledge institutional grants from Union Therapeutics for the conduct of investigator initiated clinical trials of niclosamide. MS is a shareholder of UNION Therapeutics, and AW benefits from an employee incentive scheme. The other authors declare no conflict of interest.