Cationic peptides inhibit SARS-CoV-2 cell entry

NewsGuard 100/100 Score

Heparan sulfate (HS) is a cell surface glycosaminoglycan that has been identified as a key entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in association with the well-known angiotensin-converting enzyme 2 (ACE2) receptor. Some preliminary studies have suggested that competitive inhibition or removal of HS can reduce the ability of SARS-CoV-2 to enter cells and thus lessens infection.

In a paper recently published in Pathogens, in silico affinity studies by researchers at the University of Illinois, USA, reveal several potential peptide binding sites required for HS-spike protein and ACE2-spike protein bond formation, and synthesis of suitable peptide inhibitors reveals impaired SARS-CoV-2 cell entry.  

Study: Heparan Sulfate Binding Cationic Peptides Restrict SARS-CoV-2 Entry. Image Credit: Kateryna Kon / Shutterstock
Study: Heparan Sulfate Binding Cationic Peptides Restrict SARS-CoV-2 Entry. Image Credit: Kateryna Kon / Shutterstock

In silico docking studies

HS contains a large number of negatively charged sulfate groups and therefore binds to positively charged peptide species with high affinity. Two peptides generated by the group are termed G1 and G2 (LRSRTKIIRIRH and MPRRRRIRRRQK, respectively), the first of which possesses alternating positively charged residues, while G2 bears strings of positive residues. The SARS-CoV-2 spike protein receptor binding domain (RBD), the ACE2 receptor, and the G1 and G2 peptides were modeled computationally, and the bonding interactions between the molecules were explored.

Both peptides were seen to bond with either the receptor binding domain or ACE2 in positions that would interfere with bonding between the proteins, particularly G1. Similar disruptive interactions were also observed between HS and the spike protein, which motivated the group to perform in vitro studies to test viral entry.

In vitro studies

A SARS-CoV-2 pseudovirus expressing the spike protein was generated and exposed to HEK (kidney) cells that were incubated with either peptide G1 or G2 one hour before infection. This prophylactic treatment significantly reduced pseudovirus entry at 48 hours post-infection at concentrations as low as 6.1 µg /mL, with similar results for Lund human mesencephalic (neuronal) cells. Untreated HEK cells were burdened with around 5 times as great of a viral load than those treated with 6.1 µg /mL of either peptide, and those treated with 50 µg /mL of peptide bore approximately 12.5 fold less.

LUHMES cells, in comparison, exhibited dozens fold less viral cell entry when incubated with either of the peptides, perhaps due to a differing rate of ACE2 or HS expression compared with HEK cells. The cytotoxicity of the peptides (IC50) towards HEK cells was ascertained to be 1.3 mg/mL and 1.09 mg/mL for G1 and G2, respectively, which suggests good specificity and is promising for a preclinical drug candidate.

To explore the influence of G1 and G2 on HS expression, the glycosaminoglycan was fluorescently tagged on the surface of HEK cells and subsequently exposed to the peptides. Small quantities of HS are naturally found in the nucleus, and G1-treated cells had only this source of HS remaining following treatment, having shed their external HS. Treatment with G2, however, caused internalization of HS rather than shedding. Further studies will be needed to investigate the complete mechanism behind this phenomenon.

Targeting glycoproteins such as HS is a broad-spectrum antiviral strategy, and G1 and G2 peptides have also shown efficacy in inhibiting cell entry in herpes simplex virus type 1. They bind with HS at the 3-O-sulfated heparan sulfate site. G1, in particular, demonstrates high affinity towards the TYR453 amino acid residue located on the SARS-CoV-2 receptor binding domain, which has high affinity towards the ACE2 receptor, and therefore G1 is likely to inhibit bonding. Additionally, G1 appears to induce the complete removal of HS from the cell surface, severely impairing SARS-CoV-2 cell entry.

Journal reference:
Michael Greenwood

Written by

Michael Greenwood

Michael graduated from the University of Salford with a Ph.D. in Biochemistry in 2023, and has keen research interests towards nanotechnology and its application to biological systems. Michael has written on a wide range of science communication and news topics within the life sciences and related fields since 2019, and engages extensively with current developments in journal publications.  


Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Greenwood, Michael. (2021, June 29). Cationic peptides inhibit SARS-CoV-2 cell entry. News-Medical. Retrieved on June 12, 2024 from

  • MLA

    Greenwood, Michael. "Cationic peptides inhibit SARS-CoV-2 cell entry". News-Medical. 12 June 2024. <>.

  • Chicago

    Greenwood, Michael. "Cationic peptides inhibit SARS-CoV-2 cell entry". News-Medical. (accessed June 12, 2024).

  • Harvard

    Greenwood, Michael. 2021. Cationic peptides inhibit SARS-CoV-2 cell entry. News-Medical, viewed 12 June 2024,


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Study finds Plexin-B1 could be key to Alzheimer’s treatment, enhancing glial cell response