Integrin-binding peptide ATN-161: Potential COVID-19 treatment

The ongoing COVID-19 pandemic has taken an enormous toll in terms of human lives, productivity, and economic disruption. Scientists have been working intensively to find effective and safe therapeutics for the viral infection, mostly by inhibiting the entry of the virus into the host cell. Now, a new study by researchers at Tulane University and published on the preprint server bioRxiv* in June 2020 reports the potential role of an integrin inhibitor ATN-161 to prevent ACE2-S protein binding.

Representative phase contrast microscope images of VeroE6 cells 24 hours post-infection with and without 10 µM ATN-161 treatment. Black arrows indicate some of the visible viral cytopathic effect (rounded, phase bright cells). Scale bar is 10 µM. Data represent mean ± SD,
Representative phase-contrast microscope images of VeroE6 cells 24 hours post-infection with and without 10 µM ATN-161 treatment. Black arrows indicate some of the visible viral cytopathic effect (rounded, phase bright cells). Scale bar is 10 µM.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

SARS-CoV-2 Entry into the Cell

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell via the ACE2 receptor, binding to it via the spike protein, which has a receptor-binding domain (RBD). This entry mechanism also involves integrin binding, since the spike protein has an integrin-binding motif that attaches to the RGD (arginylglycylaspartic acid) pocket on the integrin.

The Role of Integrins in SARS-CoV-2 Infection

Integrins are extracellular receptors, found in the extracellular matrix around the cells in every tissue. As such, integrins are present in the respiratory epithelium and vascular endothelium. The β-1 integrin family is also found to function in close relation to the ACE2 molecule.

ATN-161 and ACE2/ α5β1 Binding

The peptide called ATN-161, which is a fibronectin derivative, is known to bind to and block some integrins, such as α5β1. As a result, it has been used to examine the process of viral replication.

ATN-161 does not bind to the RGD site, being a non-competitive α5β1 inhibitor. The ACE2 receptor also binds non-competitively to α5β1, and not via RGD. The researchers wanted to find out if the entry of the virus is promoted by the binding of the viral spike protein to the α5β1 integrin, which is, in turn, bound to the ACE2 molecule.

This would bring the virus in proximity to the ACE2 protein. If so, the presence of ATN-161 will block SARS-CoV-2 infection by preventing integrin-binding with the spike protein, and the preliminary ACE2- α5β1 association as well.

ATN-161 Inhibits Spike/α5β1 Binding

The study used ELISA to quantify the spike protein-ACE2 and spike- α5β1 binding. First, they incubated the α5β1 integrin with both trimeric spike protein and ATN-161. The spike protein and fibronectin have almost the same affinity for the α5β1 integrin, even though fibronectin is the native ligand of this integrin. ATN-161 affects the binding of the α5β1 to the spike protein in a dose-dependent manner, the maximum inhibition being seen at 100 nM.

ATN-161 Inhibits ACE2/ α5β1 Binding

Next, they looked at the binding of ACE2 to α5β1, using a mix of ATN-161 at varying concentrations, and human ACE2 (hACE2) added to plates coated with α5β1. They found that ATN-161 inhibits the binding of ACE2 to α5β1, with increasing inhibition as the dose of ATN-161 increases. The trimeric spike protein-ACE2 binding was unaffected by the presence of ATN-161, whereas the binding of the monomeric form was inhibited.

ATN-161 Mitigates Severity of Infection

When a cell culture was exposed to SARS-CoV-2 in the presence of ATN-161, they found the latter reduced effective viral loads following infection, with an IC50 (half-maximal inhibitory concentration) of 3.16 µM, and the half-maximal effective concentration being comparable to that of the approved drug remdesivir.

Finally, they observed that when first exposed to ATN-161, infected cells remained more viable. Even at a low concentration of 1 µM, ATN was associated with a low copy number. When 10 µM of ATN-161 was used, the cytopathic effect was reduced, resulting in a lower number of rounded bright cells on phase-contrast microscopy.

Implications and Future Directions

This is the first time that the SARS-CoV-2 has been seen to interact with integrins. The study shows that the spike protein binds to both the α5β1 as well as to the α5β1-hACE2 complex. The inhibitor ATN-161 prevents this binding effectively, and in vitro experiments show that it prevents cell infection by SARS-CoV-2 as well.

When a cell culture is exposed to ATN-161 before being infected with this virus, the infected cells retain greater viability, with higher ATP production, which is a sign of cell health. The cytopathic effects produced by the virus are also less intense in such cells.

Overall, therefore, the findings indicate that this molecule should be tested in vivo for its efficacy in treating COVID-19, especially since it has already been shown to be effective therapeutically against the porcine hemagglutinating encephalomyelitis virus, which is a betacoronavirus closely related to SARS-CoV-2, and has successfully been used in human clinical trials for cancer therapy.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Journal references:

Article Revisions

  • May 18 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

Citations

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

  • APA

    Thomas, Liji. (2023, May 18). Integrin-binding peptide ATN-161: Potential COVID-19 treatment. News-Medical. Retrieved on November 13, 2024 from https://www.news-medical.net/news/20200617/Integrin-binding-peptide-ATN-161-Potential-COVID-19-treatment.aspx.

  • MLA

    Thomas, Liji. "Integrin-binding peptide ATN-161: Potential COVID-19 treatment". News-Medical. 13 November 2024. <https://www.news-medical.net/news/20200617/Integrin-binding-peptide-ATN-161-Potential-COVID-19-treatment.aspx>.

  • Chicago

    Thomas, Liji. "Integrin-binding peptide ATN-161: Potential COVID-19 treatment". News-Medical. https://www.news-medical.net/news/20200617/Integrin-binding-peptide-ATN-161-Potential-COVID-19-treatment.aspx. (accessed November 13, 2024).

  • Harvard

    Thomas, Liji. 2023. Integrin-binding peptide ATN-161: Potential COVID-19 treatment. News-Medical, viewed 13 November 2024, https://www.news-medical.net/news/20200617/Integrin-binding-peptide-ATN-161-Potential-COVID-19-treatment.aspx.

Comments

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
Post

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...
Research links COVID-19 vaccines to temporary facial palsy in over 5,000 patients