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In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment

View ORCID ProfileJesse W. Wotring, View ORCID ProfileSean M. McCarty, View ORCID ProfileKhadija Shafiq, View ORCID ProfileCharles J. Zhang, Theophilus Nguyen, View ORCID ProfileSophia R. Meyer, View ORCID ProfileReid Fursmidt, View ORCID ProfileCarmen Mirabelli, View ORCID ProfileMartin C. Clasby, View ORCID ProfileChristiane E. Wobus, View ORCID ProfileMatthew J. O’Meara, View ORCID ProfileJonathan Z. Sexton
doi: https://doi.org/10.1101/2022.06.24.497526
Jesse W. Wotring
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Sean M. McCarty
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Khadija Shafiq
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Charles J. Zhang
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Theophilus Nguyen
2Department of Internal Medicine, Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
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Sophia R. Meyer
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Reid Fursmidt
2Department of Internal Medicine, Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
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Carmen Mirabelli
3Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
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Martin C. Clasby
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
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Christiane E. Wobus
3Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
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Matthew J. O’Meara
4Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
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Jonathan Z. Sexton
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
2Department of Internal Medicine, Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
5U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
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  • For correspondence: jzsexton@med.umich.edu
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Abstract

Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide has also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro, generating interest in its use for the treatment or prevention of COVID-19. Unfortunately, there are several potential issues with using niclosamide for COVID-19, including low bioavailability, significant polypharmacology, high cellular toxicity, and unknown efficacy against emerging SARS-CoV-2 variants of concern. In this study, we used high-content imaging-based immunofluorescence assays in two different cell models to assess these limitations and evaluate the potential for using niclosamide as a COVID-19 antiviral. We show that despite promising preliminary reports, the antiviral efficacy of niclosamide overlaps with its cytotoxicity giving it a poor in vitro selectivity index for anti-SARS-CoV-2 inhibition. We also show that niclosamide has significantly variable potency against the different SARS-CoV-2 variants of concern and is most potent against variants with enhanced cell-to-cell spread including B.1.1.7. Finally, we report the activity of 33 niclosamide analogs, several of which have reduced cytotoxicity and increased potency relative to niclosamide. A preliminary structure-activity relationship analysis reveals dependence on a protonophore for antiviral efficacy, which implicates nonspecific endolysosomal neutralization as a dominant mechanism of action. Further single-cell morphological profiling suggests niclosamide also inhibits viral entry and cell-to-cell spread by syncytia. Altogether, our results suggest that niclosamide is not an ideal candidate for the treatment of COVID-19, but that there is potential for developing improved analogs with higher clinical translational potential in the future.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 24, 2022.
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In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
Jesse W. Wotring, Sean M. McCarty, Khadija Shafiq, Charles J. Zhang, Theophilus Nguyen, Sophia R. Meyer, Reid Fursmidt, Carmen Mirabelli, Martin C. Clasby, Christiane E. Wobus, Matthew J. O’Meara, Jonathan Z. Sexton
bioRxiv 2022.06.24.497526; doi: https://doi.org/10.1101/2022.06.24.497526
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In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
Jesse W. Wotring, Sean M. McCarty, Khadija Shafiq, Charles J. Zhang, Theophilus Nguyen, Sophia R. Meyer, Reid Fursmidt, Carmen Mirabelli, Martin C. Clasby, Christiane E. Wobus, Matthew J. O’Meara, Jonathan Z. Sexton
bioRxiv 2022.06.24.497526; doi: https://doi.org/10.1101/2022.06.24.497526

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