Contribution of Syndecans to the Cellular Entry of SARS-CoV-2

Int J Mol Sci. 2021 May 19;22(10):5336. doi: 10.3390/ijms22105336.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus's interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.

Keywords: SARS-CoV-2; cellular entry; coronaviruses; spike protein; syndecans.

MeSH terms

  • Amiloride / pharmacology
  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • COVID-19 / metabolism*
  • COVID-19 / virology
  • Cell Line
  • Cell Survival / drug effects
  • Epithelial Sodium Channel Blockers / pharmacology
  • Humans
  • Peptides / pharmacology
  • Protein Domains
  • Receptors, Coronavirus / metabolism*
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / pathogenicity*
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Syndecan-4 / antagonists & inhibitors
  • Syndecan-4 / metabolism
  • Syndecans / antagonists & inhibitors
  • Syndecans / metabolism*
  • Virus Internalization*


  • Angiotensin-Converting Enzyme Inhibitors
  • DX600 peptide
  • Epithelial Sodium Channel Blockers
  • Peptides
  • Receptors, Coronavirus
  • SDC4 protein, human
  • Spike Glycoprotein, Coronavirus
  • Syndecan-4
  • Syndecans
  • spike protein, SARS-CoV-2
  • Amiloride
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2