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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2020
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.
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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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