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Sialic acid-Dependent Binding and Viral Entry of SARS-CoV-2

Linh Nguyen, Kelli A. McCord, Duong T. Bui, Kim M. Bouwman, Elena N. Kitova, Dhanraj Kumawat, Gour C. Daskhan, Ilhan Tomris, Ling Han, Pradeep Chopra, Tzu-Jing Yang, Steven D. Willows, Andrew L. Mason, View ORCID ProfileTodd L. Lowary, View ORCID ProfileLori J. West, View ORCID ProfileShang-Te Danny Hsu, View ORCID ProfileS. Mark Tompkins, View ORCID ProfileGeert-Jan Boons, View ORCID ProfileRobert P. de Vries, View ORCID ProfileMatthew S. Macauley, View ORCID ProfileJohn S. Klassen
doi: https://doi.org/10.1101/2021.03.08.434228
Linh Nguyen
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Kelli A. McCord
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Duong T. Bui
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Kim M. Bouwman
2Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
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Elena N. Kitova
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Dhanraj Kumawat
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Gour C. Daskhan
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Ilhan Tomris
2Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
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Ling Han
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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Pradeep Chopra
3Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA
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Tzu-Jing Yang
4Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
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Steven D. Willows
5Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
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Andrew L. Mason
5Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
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Todd L. Lowary
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
4Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
6Institute of Biochemical Sciences, National Taiwan University, Taiwan
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  • ORCID record for Todd L. Lowary
Lori J. West
7Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
8Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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Shang-Te Danny Hsu
4Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
6Institute of Biochemical Sciences, National Taiwan University, Taiwan
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S. Mark Tompkins
9Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
10Emory-UGA Centers of Excellence for Influenza Research and Surveillance (CEIRS), Athens, GA, USA
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Geert-Jan Boons
2Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
3Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA
11Department of Chemistry, University of Georgia, Athens, GA, USA
12Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
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Robert P. de Vries
2Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
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Matthew S. Macauley
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
8Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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  • For correspondence: jsk3@ualberta.ca
John S. Klassen
1Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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  • For correspondence: jsk3@ualberta.ca
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Abstract

Emerging evidence suggests that host glycans influence infection by SARS-CoV-2. Here, we reveal that the receptor-binding domain (RBD) of the spike (S)-protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (SA), with preference for the oligosaccharide of monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind the RBD. The monomeric affinities (Kd = 100-200 μM) of gangliosides for the RBD are similar to heparan sulfate, another negatively charged glycan ligand of the RBD proposed as a viral coreceptor. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to ACE2-expressing cells is decreased upon depleting cell surface SA level using three approaches: sialyltransferase inhibition, genetic knock-out of SA biosynthesis, or neuraminidase treatment. These effects on RBD binding and pseudotyped viral entry are recapitulated with pharmacological or genetic disruption of glycolipid biosynthesis. Together, these results suggest that sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Sialic acid-Dependent Binding and Viral Entry of SARS-CoV-2
Linh Nguyen, Kelli A. McCord, Duong T. Bui, Kim M. Bouwman, Elena N. Kitova, Dhanraj Kumawat, Gour C. Daskhan, Ilhan Tomris, Ling Han, Pradeep Chopra, Tzu-Jing Yang, Steven D. Willows, Andrew L. Mason, Todd L. Lowary, Lori J. West, Shang-Te Danny Hsu, S. Mark Tompkins, Geert-Jan Boons, Robert P. de Vries, Matthew S. Macauley, John S. Klassen
bioRxiv 2021.03.08.434228; doi: https://doi.org/10.1101/2021.03.08.434228
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Sialic acid-Dependent Binding and Viral Entry of SARS-CoV-2
Linh Nguyen, Kelli A. McCord, Duong T. Bui, Kim M. Bouwman, Elena N. Kitova, Dhanraj Kumawat, Gour C. Daskhan, Ilhan Tomris, Ling Han, Pradeep Chopra, Tzu-Jing Yang, Steven D. Willows, Andrew L. Mason, Todd L. Lowary, Lori J. West, Shang-Te Danny Hsu, S. Mark Tompkins, Geert-Jan Boons, Robert P. de Vries, Matthew S. Macauley, John S. Klassen
bioRxiv 2021.03.08.434228; doi: https://doi.org/10.1101/2021.03.08.434228

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