JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis

Son, Juhee; Huang, Shimeng; Zeng, Qiru; Bricker, Traci L.; Case, James Brett; Zhou, Jinzhu; Zang, Ruochen; Liu, Zhuoming; Chang, Xinjian; Harastani, Houda H.; Chen, Lu; Castro, María Florencia Gómez; Zhao, Yongxiang; Kohio, Hinissan P.; Hou, Gaopeng; Fan, Baochao; Niu, Beibei; Guo, Rong; Rothlauf, Paul W.; Bailey, Adam L.; Wang, Xin; Shi, Pei–Yong; Martínez, Elisabeth D.; Whelan, Sean P. J.; Diamond, Michael S.; Boon, Adrianus C. M.; Li, Bin; Ding, Siyuan

doi:10.1101/2020.09.24.312165

Cited by 12 publications

(16 citation statements)

References 68 publications

(109 reference statements)

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“…In the case of Coronaviridae, nitazoxanide is effective against several animal and human strains, including the MERS-CoV in cell culture (25,34,35 (37,38). In addition, in a recent multicenter, double-blind, randomized, placebo-controlled trial of patients with mild COVID-19 nitazoxanide, whereas it did not appear to alter symptom resolution (dry cough, fever, and fatigue), was found to significantly reduce viral load, to be safe and to increase the proportion of patients testing negative for SARS-CoV-2 after 5 days of therapy compared to placebo (38).…”

Section: Nitazoxanide Is Able To Inhibit the Fusogenic Activity Of Sars-cov-2 Spike Variantsmentioning

confidence: 99%

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Riccio

Santopolo

Rossi

et al. 2021

Preprint

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The emergence of the highly-pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 (coronavirus disease-2019), has caused an unprecedented global health crisis, as well as societal and economic disruption. The SARS-CoV-2 spike (S), a surface-anchored trimeric class-I fusion glycoprotein essential for entry into host cells, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of several SARS-CoV-2 spike variants that facilitate virus spread and may affect the efficacy of recently developed vaccines, creates great concern and highlights the importance of identifying antiviral drugs to reduce SARS-CoV-2-related morbidity and mortality. Nitazoxanide, a thiazolide originally developed as an antiprotozoal agent with recognized broad-spectrum antiviral activity in-vitro and in clinical studies, was recently shown to be effective against several coronaviruses, including SARS-CoV-2. Using biochemical and pseudovirus entry assays, we now demonstrate that nitazoxanide interferes with the SARS-CoV-2 spike biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage, and hindering its fusion activity in human cells. Besides membrane fusion during virus entry, SARS-CoV-2 S-proteins in infected cells can also trigger receptor-dependent formation of syncytia, observed in-vitro and in COVID-19 patients tissues, facilitating viral dissemination between cells and possibly promoting immune evasion. Utilizing two different quantitative cell-cell fusion assays, we show that nitazoxanide is effective in inhibiting syncytia formation mediated by different SARS-CoV-2 spike variants in human lung, liver and intestinal cells. The results suggest that nitazoxanide may represent a useful tool in the fight against COVID-19 infections, inhibiting SARS-CoV-2 replication and preventing spike-mediated syncytia formation.

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Section: Nitazoxanide Is Able To Inhibit the Fusogenic Activity Of Sars-cov-2 Spike Variantsmentioning

confidence: 99%

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Riccio

Santopolo

Rossi

et al. 2021

Preprint

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“…10 ( 109 ) Baricitinib ‒ ‒ ‒ Phase 2,3,4 (2020-001854-23, 2020-001354-22, NCT04358614) 232 Fig. 10 ( 110 ) Nitazoxanide In vitro 2.12 >35.53 Phase 2, 3 (NCT04341493, NCT01056380, NCT04348409) 19 , 238 In vitro 4.90 >300 237 Fig. 10 ( 111 ) JIB-04 In vitro 0.695 >300 Preclinical 237 Fig.…”

Section: Sars-cov-2 Life Cycle and Potential Targets For The Development Of Small-molecule Inhibitors Against Sars-cov-2 Infectionmentioning

confidence: 99%

“…10 ( 110 ) Nitazoxanide In vitro 2.12 >35.53 Phase 2, 3 (NCT04341493, NCT01056380, NCT04348409) 19 , 238 In vitro 4.90 >300 237 Fig. 10 ( 111 ) JIB-04 In vitro 0.695 >300 Preclinical 237 Fig. 10 ( 112 ) Fenofibrate In vitro 20 >100 Preclinical 187 Fig.…”

Section: Sars-cov-2 Life Cycle and Potential Targets For The Development Of Small-molecule Inhibitors Against Sars-cov-2 Infectionmentioning

confidence: 99%

“…JIB-04 is a pan-Jumonji histone demethylase inhibitor 236 . Neither drug induced cytotoxicity at 300 μmol/L and thus had excellent selectivity index (SI > 150) 237 . A recent review evaluated nine clinical trials of nitazoxanide for assessing the safety, cost and potential use of this drug for COVID-19 238 .…”

Section: Small-molecule Sars-cov-2 Inhibitors Targeting Host Proteinsmentioning

confidence: 99%

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Recent advances in developing small-molecule inhibitors against SARS-CoV-2

Xiang

Wang

et al. 2022

Acta Pharmaceutica Sinica B

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The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.

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“…Controversies regarding treatment during early (first stage) COVID-19 include supposed lack of a pharmacological option with clear benefits. Hydroxychloroquine (HCQ), nitazoxanide (NIT) and ivermectin (IVE), in association with azithromycin (AZI), are popular drugs largely used as off label therapies for COVID-19, that have demonstrated in vitro antiviral activity and preliminary observational reports as being beneficial against COVID-19, when used until seven days after beginning of symptoms, before respiratory complications and hospitalization (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Use of any of these drugs further in the disease, during second and third stages, have not demonstrated benefits or conflicting findings (2;30).…”

Section: Introductionmentioning

confidence: 99%

Early COVID-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced Symptoms Compared to Known Outcomes in Untreated Patients.

Cadegiani

Goren²,

Wambier

et al. 2020

Preprint

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Background: While there was a lack of pharmacological interventions proven to be effective in early, outpatient settings for COVID-19, in a prospective, open-label observational study (pre-AndroCoV Trial) the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated similar effects, and apparent improvement of outcomes compared to untreated patients. The unexpected apparent positive results led to ethical questions on the employment of further full placebo-control studies in early stage COVID-19. The objective of the present study was to elucidate whether the conduction of a full placebo-control RCT was still ethically viable, through a comparative analysis with two control-groups.Materials and methods: Active group (AG) consisted of mild-to-moderate early stage COVID-19 patients enrolled in the Pre AndroCoV-Trial, treated with nitazoxanide ivermectin, or hydroxychloroquine in selected cases, in association with azithromycin. Vitamin D, vitamin C, zinc, glucocorticoids and anticoagulants, when clinically recommended. Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients from the same population as those from the Pre-AndroCoV Trial, and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes, based on a thorough and structured review of articles indexed in PubMed and MEDLINE and statements by official government agencies and specific medical societies. For both CGs, patients were matched for proportion between sex, age, obesity and other comorbidities. Results: Compared to CG1 and CG2, AG showed a reduction of 31.5 to 36.5% in viral shedding (p < 0.0001), 70 to 85% and 70 to 73% in duration of COVID-19 clinical symptoms when including and not including anosmia and ageusia, respectively ((p < 0.0001 for both), and 100% in respiratory complications through the parameters of the Brescia COVID-19 Respiratory Scale (p < 0.0001). For every 1,000 confirmed cases for COVID-19, a minimum of 140 patients were prevented from hospitalization (p < 0.0001), 50 from mechanical ventilation, and five deaths, when comparing to age-, sex- and comorbidity-matched non-treated patients with similar initial disease severity at the moment of diagnosis.Conclusion: Apparent benefits of the combination between early detection and early pharmacological approaches for COVID-19 demonstrated to be consistent when when compared to different control groups of untreated patients. The potential benefits could allow a large number of patients prevented from hospitalizations, deaths and persistent symptoms after COVID-19 remission. The potential impact on COVID-19 disease course and numbers of negative outcomes and the well-established safety profile of the drugs proposed by the Pre-AndroCoV Trial led to ethical questions regarding the conduction of further placebo control randomized clinical trials (RCTs) for early COVID-19. Early pharmacological approaches including azithromycin in combination with any of the options between nitazoxanide, ivermectin or optionally hydroxychloroquine should be considered for those diagnosed with COVID-19 presenting less than seven days of symptoms. Of the three drugs, we opted for nitazoxanide, due to more extensive demonstration of in vitro and in vivoantiviral activity, proven efficacy against other viruses in humans, and steadier safety profile.

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JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis

Cited by 12 publications

References 68 publications

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

Early COVID-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced Symptoms Compared to Known Outcomes in Untreated Patients.

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