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

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 preventio...

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Autores principales: Wotring, Jesse W., McCarty, Sean M., Shafiq, Khadija, Zhang, Charles J., Nguyen, Theophilus, Meyer, Sophia R., Fursmidt, Reid, Mirabelli, Carmen, Clasby, Martin C., Wobus, Christiane E., O’Meara, Matthew J., Sexton, Jonathan Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9412300/
https://www.ncbi.nlm.nih.gov/pubmed/36016172
http://dx.doi.org/10.3390/vaccines10081284
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author Wotring, Jesse W.
McCarty, Sean M.
Shafiq, Khadija
Zhang, Charles J.
Nguyen, Theophilus
Meyer, Sophia R.
Fursmidt, Reid
Mirabelli, Carmen
Clasby, Martin C.
Wobus, Christiane E.
O’Meara, Matthew J.
Sexton, Jonathan Z.
author_facet Wotring, Jesse W.
McCarty, Sean M.
Shafiq, Khadija
Zhang, Charles J.
Nguyen, Theophilus
Meyer, Sophia R.
Fursmidt, Reid
Mirabelli, Carmen
Clasby, Martin C.
Wobus, Christiane E.
O’Meara, Matthew J.
Sexton, Jonathan Z.
author_sort Wotring, Jesse W.
collection PubMed
description 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 the B.1.1.7 (alpha) variant. 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.
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spelling pubmed-94123002022-08-27 In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment Wotring, Jesse W. McCarty, Sean M. Shafiq, Khadija Zhang, Charles J. Nguyen, Theophilus Meyer, Sophia R. Fursmidt, Reid Mirabelli, Carmen Clasby, Martin C. Wobus, Christiane E. O’Meara, Matthew J. Sexton, Jonathan Z. Vaccines (Basel) Article 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 the B.1.1.7 (alpha) variant. 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. MDPI 2022-08-09 /pmc/articles/PMC9412300/ /pubmed/36016172 http://dx.doi.org/10.3390/vaccines10081284 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wotring, Jesse W.
McCarty, Sean M.
Shafiq, Khadija
Zhang, Charles J.
Nguyen, Theophilus
Meyer, Sophia R.
Fursmidt, Reid
Mirabelli, Carmen
Clasby, Martin C.
Wobus, Christiane E.
O’Meara, Matthew J.
Sexton, Jonathan Z.
In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title_full In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title_fullStr In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title_full_unstemmed In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title_short In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
title_sort in vitro evaluation and mitigation of niclosamide’s liabilities as a covid-19 treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9412300/
https://www.ncbi.nlm.nih.gov/pubmed/36016172
http://dx.doi.org/10.3390/vaccines10081284
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