Heparan sulfate proteoglycans as attachment factor for SARS-CoV-2

Area of Science:

• Virology
• Glycobiology
• Drug Discovery

Background:

• The global SARS-CoV-2 pandemic necessitates novel therapeutic interventions.
• Heparan sulfate (HS) is a complex carbohydrate found on cell surfaces, implicated in various biological processes.

Approach:

• Utilized microarray binding assays with an HS oligosaccharide library to investigate SARS-CoV-2 spike protein interactions.
• Employed surface plasmon resonance (SPR) to quantify binding affinities between SARS-CoV-2 components and heparin.
• Conducted tissue staining studies to assess the role of heparan sulfate proteoglycans (HSPGs) in viral attachment.

Key Points:

• The SARS-CoV-2 receptor binding domain (RBD) binds HS in a length- and sequence-dependent manner, with specific hexa- and octa-saccharides being optimal ligands.
• The full SARS-CoV-2 spike protein exhibits significantly higher affinity for heparin (KD = 55 nM) than the RBD alone (KD = 1 uM).
• Heparin binding does not impede angiotensin-converting enzyme 2 (ACE2) interaction or spike protein processing, suggesting a distinct role in initial attachment.

Conclusions:

• Heparan sulfate (HS) acts as a crucial initial attachment point for SARS-CoV-2 entry into host cells.
• Heparan sulfate proteoglycans (HSPGs) are identified as critical viral attachment factors.
• HS oligosaccharides represent a promising therapeutic strategy for inhibiting SARS-CoV-2 cell entry.