COVID-19 virus uses heparan sulfate to enter cells.

The spike protein of SARS-CoV-2 must bind both the ACE2 receptor and heparan sulfate to gain entry into human cells. Credit: University of California – San Diego

A molecule known as ACE2 sits like a doorknob on the outer surfaces of cells that line the lungs. Since January 2020, researchers have discovered that SARS-CoV-2, a novel coronovirus that causes COVID-19, primarily uses ACE2 to enter these cells and establish respiratory infections. Finding a way to close the interaction between the virus and dorknob as a means of treating the infection has become the goal of many research studies.

Researchers at the University of California San Diego School of Medicine have discovered that SARS-CoV-2 cannot capture ACE2 without a carbohydrate called heparan sulfate, which is also found on lung cell surfaces and is responsible for viral penetration. -Supports as Receptor.

“ACE2 is only part of the story,” Jeffrey Esko, PhD, distinguished professor of cellular and molecular medicine at UC San Diego School of Medicine and co-director of the Center for Glycology Research and Training. “It’s not the whole picture.”

Esko’s study, published on September 14, 2020 CellCOVID-19 introduces a potential new approach to prevention and treatment.

The team demonstrated two approaches that could reduce the ability of SARS-CoV-2 to approximately 80 to 90 percent of human cells cultured in the laboratory: 1) removing heparin sulfate with enzymes or 2) using heparin as bait. Does as bait and tying for. Coronovirus away from human cells. Heparin, a form of heparan sulfate, is already a widely used drug to prevent and treat blood clots, suggesting that the food and drug administration is used to reduce virus infection. The approved drug can be returned.

Esco’s team has studied heparan sulfate for a long time and the role it plays in health and disease. He led the study to scholar Thomas Mandel Clausen, Ph.D., and postdoctoral researcher Daniel Sandowal, Ph.D. Although it is not necessary to focus on the virus in Esko’s laboratory, Clausen previously studied how the malaria parasite interacts with the related carbohydrates on human cells and Sandowal had been interested in the virus since he was a graduate student – he Still keeps up with the latest virology research for fun.

One Friday afternoon in March 2020, Clausen was exhausted and, he was discontinuing his experiments. Instead, he misused the latest research about SARS-CoV-2. When he came across an early study that suggested interactions between coronovirus spike proteins – the virus uses “hands” to grab ACE2 doorknob- and another carbohydrate related to heparan sulfate.

“I ran to Daniel to ask him to look at the study – and of course, he was already thinking the same thing,” said Klausen, who is also an associate professor at the University of Copenhagen in Denmark .

Within a week, the team was testing their theories in the laboratory. They found that the SARS-CoV-2 spike protein binds heparin. The team also drilled to uncover the exact part of the SARS-CoV-2 spike protein that interacts with the heparin-receptor binding domain. When heparin is bound, the receptor binding domain opens and binding to ACE2 increases. They found that the virus binds heparan sulfate on both the cell surface and ACE2 to grow human lung cells in a laboratory dish.

With the establishment of this viral entry mechanism, researchers set next about trying to disrupt it. They found that enzymes that remove heparan sulfate from the cell surface prevent SARS-CoV-2 from entering cells. Similarly, treatment with heparin also prevented infection. Heparin treatment acted as an anti-viral in the doses currently being given to patients, even when researchers removed the anticoagulant region of the protein – the part responsible for preventing blood clots.

Esko said the findings are still far from translating into a COVID-19 treatment for people. Researchers will need to test heparin and heparan sulfate inhibitors in animal models of SARS-CoV-2 infection. In a related study, UC San Diego scientists are also exploring the role of the human microbiome, which includes bacteria that live on the body, play a role in changing heparan sulfate and thus a person’s susceptibility to COVID-19 Affect.

“This is one of the most exciting periods of my career — about heparan sulfate and the resources we have developed over the years, all of which have come together with various experts from many institutions who were quick to collaborate. And share ideas, ”said Essco. “If there is a silver lining to this epidemic, I hope that the scientific community will continue to work that way faster to overcome other problems.”

Designing peptide inhibitors for possible COVID-19 treatment

more information:
Thomas Mandel Clausen et al, SARS-CoV-2 infection depends on cellular heparan sulfate and ACEE2, Cell (2020). DOI: 10.1016 / j.cell.2020.09.033

Journal Information:

Provided by University of California – San Diego

Quotes: COVID-19 virus uses heparan sulfate to enter cells (2020, September 15) 16 Retrieved September 2020

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