Inhibition Of SARS-CoV-2 Viral Entry Upon Blocking N- And O ... - ELife

Read the most recent version of this article. Version of RecordNovember 24, 2020 Accepted ManuscriptOctober 26, 2020

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1. Qi Yang
2. Thomas A Hughes
3. Anju Kelkar
4. Xinheng Yu
5. Kai Cheng
6. Sheldon Park
7. Wei-Chiao Huang
8. Jonathan F Lovell
9. Sriram Neelamegham

(2020) Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration eLife 9:e61552. https://doi.org/10.7554/eLife.61552

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The Spike protein of SARS-CoV-2, its receptor binding domain (RBD), and its primary receptor ACE2 are extensively glycosylated. The impact of this post-translational modification on viral entry is yet unestablished. We expressed different glycoforms of the Spike-protein and ACE2 in CRISPR-Cas9 glycoengineered cells, and developed corresponding SARS-CoV-2 pseudovirus. We observed that N- and O-glycans had only minor contribution to Spike-ACE2 binding. However, these carbohydrates played a major role in regulating viral entry. Blocking N-glycan biosynthesis at the oligomannose stage using both genetic approaches and the small molecule kifunensine dramatically reduced viral entry into ACE2 expressing HEK293T cells. Blocking O-glycan elaboration also partially blocked viral entry. Mechanistic studies suggest multiple roles for glycans during viral entry. Among them, inhibition of N-glycan biosynthesis enhanced Spike-protein proteolysis. This could reduce RBD presentation on virus, lowering binding to host ACE2 and decreasing viral entry. Overall, chemical inhibitors of glycosylation may be evaluated for COVID-19.

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All data generated or analysed during this study are included in the manuscript and supporting files. All plasmids generated by the authors will be deposited at Addgene.

Author details

1. Qi Yang

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   Qi Yang, Co-author of a provisional patent application.(63/079,667).

2. Thomas A Hughes

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   Thomas A Hughes, Co-author of a provisional patent application.(63/079,667). "This ORCID iD identifies the author of this article:" 0000-0002-7887-6876

3. Anju Kelkar

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   Anju Kelkar, Co-author of a provisional patent application.(63/079,667).

4. Xinheng Yu

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   No competing interests declared.

5. Kai Cheng

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   No competing interests declared.

6. Sheldon Park

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   No competing interests declared.

7. Wei-Chiao Huang

   Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   No competing interests declared.

8. Jonathan F Lovell

   Department of Biomedical Engineering, State University of New York at Buffalo, Buffalo, United States

   Competing interests

   No competing interests declared. "This ORCID iD identifies the author of this article:" 0000-0002-9052-884X

9. Sriram Neelamegham

   Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, United States

   For correspondence

   [email protected]

   Competing interests

   Sriram Neelamegham, Co-author of a provisional patent application.(63/079,667). "This ORCID iD identifies the author of this article:" 0000-0002-1371-8500

• Sriram Neelamegham

• Sriram Neelamegham

• Sriram Neelamegham

• Sheldon Park
• Sriram Neelamegham

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

© 2020, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

• 9,589 views
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• 202 citations

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• 202 citations for umbrella DOI https://doi.org/10.7554/eLife.61552

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1. Qi Yang
2. Thomas A Hughes
3. Anju Kelkar
4. Xinheng Yu
5. Kai Cheng
6. Sheldon Park
7. Wei-Chiao Huang
8. Jonathan F Lovell
9. Sriram Neelamegham

(2020) Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration eLife 9:e61552. https://doi.org/10.7554/eLife.61552

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https://doi.org/10.7554/eLife.61552

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• Biochemistry and Chemical Biology
• Microbiology and Infectious Disease

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• Human
• Viruses

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