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Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 1...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433531/ https://www.ncbi.nlm.nih.gov/pubmed/34413211 http://dx.doi.org/10.1073/pnas.2105815118 |
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author | Mirabelli, Carmen Wotring, Jesse W. Zhang, Charles J. McCarty, Sean M. Fursmidt, Reid Pretto, Carla D. Qiao, Yuanyuan Zhang, Yuping Frum, Tristan Kadambi, Namrata S. Amin, Anya T. O’Meara, Teresa R. Spence, Jason R. Huang, Jessie Alysandratos, Konstantinos D. Kotton, Darrell N. Handelman, Samuel K. Wobus, Christiane E. Weatherwax, Kevin J. Mashour, George A. O’Meara, Matthew J. Chinnaiyan, Arul M. Sexton, Jonathan Z. |
author_facet | Mirabelli, Carmen Wotring, Jesse W. Zhang, Charles J. McCarty, Sean M. Fursmidt, Reid Pretto, Carla D. Qiao, Yuanyuan Zhang, Yuping Frum, Tristan Kadambi, Namrata S. Amin, Anya T. O’Meara, Teresa R. Spence, Jason R. Huang, Jessie Alysandratos, Konstantinos D. Kotton, Darrell N. Handelman, Samuel K. Wobus, Christiane E. Weatherwax, Kevin J. Mashour, George A. O’Meara, Matthew J. Chinnaiyan, Arul M. Sexton, Jonathan Z. |
author_sort | Mirabelli, Carmen |
collection | PubMed |
description | The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19. |
format | Online Article Text |
id | pubmed-8433531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-84335312021-09-28 Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 Mirabelli, Carmen Wotring, Jesse W. Zhang, Charles J. McCarty, Sean M. Fursmidt, Reid Pretto, Carla D. Qiao, Yuanyuan Zhang, Yuping Frum, Tristan Kadambi, Namrata S. Amin, Anya T. O’Meara, Teresa R. Spence, Jason R. Huang, Jessie Alysandratos, Konstantinos D. Kotton, Darrell N. Handelman, Samuel K. Wobus, Christiane E. Weatherwax, Kevin J. Mashour, George A. O’Meara, Matthew J. Chinnaiyan, Arul M. Sexton, Jonathan Z. Proc Natl Acad Sci U S A Biological Sciences The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19. National Academy of Sciences 2021-09-07 2021-08-19 /pmc/articles/PMC8433531/ /pubmed/34413211 http://dx.doi.org/10.1073/pnas.2105815118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Mirabelli, Carmen Wotring, Jesse W. Zhang, Charles J. McCarty, Sean M. Fursmidt, Reid Pretto, Carla D. Qiao, Yuanyuan Zhang, Yuping Frum, Tristan Kadambi, Namrata S. Amin, Anya T. O’Meara, Teresa R. Spence, Jason R. Huang, Jessie Alysandratos, Konstantinos D. Kotton, Darrell N. Handelman, Samuel K. Wobus, Christiane E. Weatherwax, Kevin J. Mashour, George A. O’Meara, Matthew J. Chinnaiyan, Arul M. Sexton, Jonathan Z. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title | Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title_full | Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title_fullStr | Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title_full_unstemmed | Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title_short | Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 |
title_sort | morphological cell profiling of sars-cov-2 infection identifies drug repurposing candidates for covid-19 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433531/ https://www.ncbi.nlm.nih.gov/pubmed/34413211 http://dx.doi.org/10.1073/pnas.2105815118 |
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