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Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro
The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-CoV and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373127/ https://www.ncbi.nlm.nih.gov/pubmed/32699847 http://dx.doi.org/10.1101/2020.07.14.202549 |
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author | Zhang, Qi Chen, Catherine Z. Swaroop, Manju Xu, Miao Wang, Lihui Lee, Juhyung Wang, Amy Q. Pradhan, Manisha Hagen, Natalie Chen, Lu Shen, Min Luo, Zhiji Xu, Xin Xu, Yue Huang, Wenwei Zheng, Wei Ye, Yihong |
author_facet | Zhang, Qi Chen, Catherine Z. Swaroop, Manju Xu, Miao Wang, Lihui Lee, Juhyung Wang, Amy Q. Pradhan, Manisha Hagen, Natalie Chen, Lu Shen, Min Luo, Zhiji Xu, Xin Xu, Yue Huang, Wenwei Zheng, Wei Ye, Yihong |
author_sort | Zhang, Qi |
collection | PubMed |
description | The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-CoV and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, facilitates the attachment of viral particles to the cell surface to promote cell entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry, and reveals drugs capable of targeting this important step in the viral life cycle. |
format | Online Article Text |
id | pubmed-7373127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-73731272020-07-22 Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro Zhang, Qi Chen, Catherine Z. Swaroop, Manju Xu, Miao Wang, Lihui Lee, Juhyung Wang, Amy Q. Pradhan, Manisha Hagen, Natalie Chen, Lu Shen, Min Luo, Zhiji Xu, Xin Xu, Yue Huang, Wenwei Zheng, Wei Ye, Yihong bioRxiv Article The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-CoV and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, facilitates the attachment of viral particles to the cell surface to promote cell entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry, and reveals drugs capable of targeting this important step in the viral life cycle. Cold Spring Harbor Laboratory 2020-09-18 /pmc/articles/PMC7373127/ /pubmed/32699847 http://dx.doi.org/10.1101/2020.07.14.202549 Text en https://creativecommons.org/publicdomain/zero/1.0/This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license (https://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Article Zhang, Qi Chen, Catherine Z. Swaroop, Manju Xu, Miao Wang, Lihui Lee, Juhyung Wang, Amy Q. Pradhan, Manisha Hagen, Natalie Chen, Lu Shen, Min Luo, Zhiji Xu, Xin Xu, Yue Huang, Wenwei Zheng, Wei Ye, Yihong Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title | Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title_full | Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title_fullStr | Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title_full_unstemmed | Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title_short | Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro |
title_sort | heparan sulfate assists sars-cov-2 in cell entry and can be targeted by approved drugs in vitro |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373127/ https://www.ncbi.nlm.nih.gov/pubmed/32699847 http://dx.doi.org/10.1101/2020.07.14.202549 |
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