Medical Health Cluster

22 julio, 2021

Can Heparin Play a Role in Stopping COVID-19 Variants?

Researchers have identified a new binding site on the spike protein of SARS-CoV-2, the virus that causes COVID-19.

They believe the new binding site could be a key part of the process involved in the virus infecting human cells, giving a new target for possible intervention.

The new binding site is also believed to be important in regard to the many different mutations of the virus as it occurs on the part of the spike protein that frequently mutates.

The new site — known as the N-terminal domain — facilitates binding of the viral spike protein to heparan sulphate on human cell surfaces, which the researchers note is generally the first step in a cascade of interactions the virus needs to initiate an infection and enter the cell.

The scientists, led by Zachariah Schuurs, PhD, Queensland University of Technology (QUT), Brisbane, Australia, are using computational simulation models to try to identify agents that could block the binding of the spike protein to heparan sulfate, with heparin-type molecules being the prime candidates.

The study was published recently in Computational and Structural Biotechnology Journal.

New Discovery

The researchers note that the role of the SARS-CoV-2 spike glycoprotein in virus infection makes it a key target for the development of antiviral drugs and vaccines. Accordingly, understanding how particular mutations in this glycoprotein may affect virus infection is a key part of the drug discovery process.

Senior author Neha Gandhi, PhD, from the QUT Centre for Genomics and Personalised Health, told Medscape Medical News that it has been known for some time that the spike protein binds to the ACE2 receptor on human cells to gain entry to those cells. However, recent evidence suggests the heparan sulphate proteoglycan receptor on the extracellular matrix of human cells is also involved in this interaction.

“The spike protein on the SARS-CoV-2 virus is covered by a layer of sugars.  This glycan shield is positively charged and attracts the negatively [charged] heparan sulfate proteoglycan receptor,” she said.

“We are using computational techniques to model how the COVID-19 spike protein binds to the heparan sulfate receptor. We have found that it can bind in multiple places all over the spike protein.”

Gandhi notes that two binding sites for heparan sulfate proteoglycan on the spike protein are already known. One is called the receptor binding site, which is the same site that binds to ACE2. The second one is known as the furin cleavage site.

“We have now identified a third binding site called the N-terminal domain which we believe may be the most important, as it is the site for most of the variant strains. The mutations occur at this site,” Gandhi said. The researchers believe this site is particularly pertinent to the South African strain (B.1.351) mutations of the virus.

“If we understand how the heparan sulfate proteoglycan binds to the spike protein we can potentially use similar molecules to inhibit that interaction,” said Gandhi.

Standard Heparin Won’t Work

The researchers are focusing on molecules similar to heparin as possible candidates to block the interaction.

“In our study, we can clearly see that the heparin molecule, which comes from the same family as heparan sulfate proteoglycan but has slightly different sulphur chemistry, can bind to this N-terminal domain receptor,” she added.

However, Gandhi pointed out that the heparin used as an anticoagulant in clinical practice is too small to be an efficient inhibitor.

The researchers are looking for a larger molecule that can span across all the heparan sulfate proteoglycan binding sites on the SARS-CoV-2 spike protein.

“The standard heparin anticoagulant only has five sugars. We tested a heparin molecule with 16 sugars, which is mid-size. But ideally, we would need something even bigger than that,” said Gandhi.

“Our research indicates that molecules that mimic the 3D structure of heparin with different sulphur chemistry might be potential broad-spectrum antiviral drugs for COVID-19 and other emerging viral threats via direct interaction with the virus itself,” she added.

Potential Candidates

“Overall, our work shows the importance of taking into account the glycan shield when conducting molecular dynamics simulations of the SARS-CoV-2 spike protein, as it can act to prevent binding to certain regions of the protein and directly interact with some docked ligands. Such interactions may be missed when conducting studies without glycosylation being included,” the investigators write.

“By considering the glycan shield, the prediction of important sites involved in molecular interactions and possibly immune recognition is improved,” they add.

They mention two heparan sulfate mimetics currently in development for other indications that would be interesting to test against the SARS-CoV-2 virus.  These are Sanofi’s SR123781 and a product known as PI-88, which is said to have antiviral effects against Dengue virus and flavivirus encephalitis.

“This work has revealed a putative multi-contact binding

mechanism of heparan sulfate to the SARS-CoV-2 spike protein. This highlights alternative ways that heparin and heparan sulfate mimetics could contribute to treatment of COVID-19, other than preventing coagulation and micro-thrombi formation,” they conclude.

The QUT researchers are working in collaboration with scientists at the University of Queensland, Curtin University, and Zucero Therapeutics in Australia. Collaborators at the University of Liverpool and Keele University in the UK conducted laboratory experiments, which confirmed the hypothesis.

The authors have disclosed no relevant financial relationships.

Comput Struct Biotechnol J. Published online May 4, 2021. Full text

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Créditos: Comité científico Covid

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