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Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro.
Zhang, Qi; Chen, Catherine Zhengzheng; Swaroop, Manju; Xu, Miao; Wang, Lihui; Lee, Juhyung; Wang, Amy Qiu; Pradhan, Manisha; Hagen, Natalie; Chen, Lu; Shen, Min; Luo, Zhiji; Xu, Xin; Xu, Yue; Huang, Wenwei; Zheng, Wei; Ye, Yihong.
  • Zhang Q; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Chen CZ; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Swaroop M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Xu M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Wang L; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Lee J; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Wang AQ; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Pradhan M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Hagen N; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Chen L; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Shen M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Luo Z; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Xu X; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Xu Y; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Huang W; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Zheng W; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
  • Ye Y; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. yihongy@mail.nih.gov.
Cell Discov ; 6(1): 80, 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-912895
Semantic information from SemMedBD (by NLM)
1. Pharmaceutical Preparations INTERACTS_WITH Heparitin Sulfate
Subject
Pharmaceutical Preparations
Predicate
INTERACTS_WITH
Object
Heparitin Sulfate
2. 2019 novel coronavirus INTERACTS_WITH COVID-19
Subject
2019 novel coronavirus
Predicate
INTERACTS_WITH
Object
COVID-19
3. Cell Count USES Incubated
Subject
Cell Count
Predicate
USES
Object
Incubated
4. Heparitin Sulfate PART_OF Cell surface
Subject
Heparitin Sulfate
Predicate
PART_OF
Object
Cell surface
5. Genes AFFECTS Heparan Sulfate Biosynthesis
Subject
Genes
Predicate
AFFECTS
Object
Heparan Sulfate Biosynthesis
6. Heparitin Sulfate DISRUPTS Virus Internalization
Subject
Heparitin Sulfate
Predicate
DISRUPTS
Object
Virus Internalization
7. Heparitin Sulfate AUGMENTS Virus Internalization
Subject
Heparitin Sulfate
Predicate
AUGMENTS
Object
Virus Internalization
8. sunitinib DISRUPTS Virus Internalization
Subject
sunitinib
Predicate
DISRUPTS
Object
Virus Internalization
9. 2019 novel coronavirus CAUSES Cytopathogenic Effec
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Cytopathogenic Effec
10. Pharmaceutical Preparations INTERACTS_WITH Heparitin Sulfate
Subject
Pharmaceutical Preparations
Predicate
INTERACTS_WITH
Object
Heparitin Sulfate
11. 2019 novel coronavirus INTERACTS_WITH COVID-19
Subject
2019 novel coronavirus
Predicate
INTERACTS_WITH
Object
COVID-19
12. Cell Count USES Incubated
Subject
Cell Count
Predicate
USES
Object
Incubated
13. Heparitin Sulfate PART_OF Cell surface
Subject
Heparitin Sulfate
Predicate
PART_OF
Object
Cell surface
14. Genes AFFECTS Heparan Sulfate Biosynthesis
Subject
Genes
Predicate
AFFECTS
Object
Heparan Sulfate Biosynthesis
15. Heparitin Sulfate DISRUPTS Virus Internalization
Subject
Heparitin Sulfate
Predicate
DISRUPTS
Object
Virus Internalization
16. Heparitin Sulfate AUGMENTS Virus Internalization
Subject
Heparitin Sulfate
Predicate
AUGMENTS
Object
Virus Internalization
17. sunitinib DISRUPTS Virus Internalization
Subject
sunitinib
Predicate
DISRUPTS
Object
Virus Internalization
18. 2019 novel coronavirus CAUSES Cytopathogenic Effect, Viral
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Cytopathogenic Effect, Viral
ABSTRACT
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, and facilitates the attachment of Spike-bearing viral particles to the cell surface to promote viral 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.

Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Language: English Journal: Cell Discov Year: 2020

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Language: English Journal: Cell Discov Year: 2020
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