OmniVira

Sialic acid-containing glycolipids mediate binding and viral entry of SARS-CoV-2.

Linh Nguyen1 Kelli A McCord1 Duong T Bui1 Kim M Bouwman2 Elena N Kitova1 Mohamed Elaish3,4 Dhanraj Kumawat1 Gour C Daskhan1 Ilhan Tomris2 Ling Han1 Pradeep Chopra5 Tzu-Jing Yang6 Steven D Willows7 Andrew L Mason7 Lara K Mahal1 Todd L Lowary1,6,8 Lori J West9,10 Shang-Te Danny Hsu6,8 Tom Hobman3,10 Stephen M Tompkins11,12 Geert-Jan Boons2,5,13,14 Robert P de Vries2 Matthew S Macauley15,16 John S Klassen17
Affiliations 17 institutions
  1. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
  2. Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
  3. Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada.
  4. Poultry Disease Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
  5. Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
  6. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  7. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
  8. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
  9. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
  10. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
  11. Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA.
  12. Emory-UGA Centers of Excellence for Influenza Research and Surveillance (CEIRS), Athens, GA, USA.
  13. Department of Chemistry, University of Georgia, Athens, GA, USA.
  14. Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands.
  15. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. [email protected].
  16. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada. [email protected].
  17. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. [email protected].
PMID34754101 DOI10.1038/s41589-021-00924-1 Year2022 Journal Nature chemical biology Nat Chem Biol Languageeng Statusppublish

Abstract

Emerging evidence suggests that host glycans influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal that the receptor-binding domain (RBD) of the spike (S) protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (Sia), with preference for monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind to the RBD. The monomeric affinities (Kd = 100-200 μM) of gangliosides for the RBD are similar to another negatively charged glycan ligand of the RBD proposed as a viral co-receptor, heparan sulfate (HS) dp2-dp6 oligosaccharides. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to angiotensin-converting enzyme 2 (ACE2)-expressing cells is decreased following depletion of cell surface Sia levels using three approaches: sialyltransferase (ST) inhibition, genetic knockout of Sia biosynthesis, or neuraminidase treatment. These effects on RBD binding and both pseudotyped and authentic SARS-CoV-2 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.

Supporting text Virus Host Location
Angiotensin-Converting Enzyme 2 177 Binding Sites 89 Glycolipids 1 Humans 1440 SARS-CoV-2 453 Sialic Acids 29 Spike Glycoprotein, Coronavirus 274 ACE2 protein, human 87 spike protein, SARS-CoV-2 157

Evidence records

1 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE5356 Molecular Adaptation
Key finding

The receptor-binding domain of the SARS-CoV-2 spike protein binds sialylated gangliosides with affinity comparable to heparan sulfate, suggesting adaptation for multiple negatively charged glycan interactions that facilitate viral entry.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

Here, we reveal that the receptor-binding domain (RBD) of the spike (S) protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (Sia), with preference for monosialylated gangliosides. The monomeric affinities (Kd = 100-200 μM) of gangliosides for the RBD are similar to another negatively charged glycan ligand of the RBD proposed as a viral co-receptor, heparan sulfate (HS) dp2-dp6 oligosaccharides.

Genes or proteins
receptor-binding domain | spike protein
Receptors
heparan sulfate | sialylated gangliosides
Host factors
sialic acid-containing glycolipids
Mechanism types
receptor binding | host entry