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

Now the researchers have discovered that SARS-CoV-2 can't grab onto ACE2 without a carbohydrate called heparan sulfate, which is also found on lung cell surfaces and acts as a co-receptor for viral entry.

"ACE2 is only part of the story," said the senior author. "It isn't the whole picture." The study, published in Cell, introduces a potential new approach for preventing and treating COVID-19.

The team demonstrated two approaches that can reduce the ability of SARS-CoV-2 to infect human cells cultured in the lab by approximately 80 to 90 percent: 1) removing heparan sulfate with enzymes or 2) using heparin as bait to lure and bind the coronavirus away from human cells. Heparin, a form of heparan sulfate, is already a widely used medication to prevent and treat blood clots, suggesting that a Food and Drug Administration-approved drug might be repurposed to reduce virus infection.

The team discovered that the SARS-CoV-2 spike protein binds to heparin. The team also drilled down to uncover the exact part of the SARS-CoV-2 spike protein that interacts with heparin -- the receptor binding domain. When heparin is bound, the receptor binding domain opens up and increases binding to ACE2. The virus, they found, must bind both heparan sulfate on the cell surface and ACE2 in order to get inside human lung cells grown in a laboratory dish.

With this viral entry mechanism established, the researchers next set about trying to disrupt it. They found that enzymes that remove heparan sulfate from cell surfaces prevent SARS-CoV-2 from gaining entry into cells. Likewise, treatment with heparin also blocked infection. The heparin treatment worked as an anti-viral at doses currently given to patients, even when the researchers removed the anticoagulant region of the protein -- the part responsible for preventing blood clots.

The findings are still far from translating into a COVID-19 treatment for people, said the author. Researchers will need to test heparin and heparan sulfate inhibitors in animal models of SARS-CoV-2 infection. In a related study, scientists are also exploring the role human microbiomes, including the bacteria that live in and on the body, play in altering heparan sulfate and thus influencing a person's susceptibility to COVID-19.

"This is one of the most exciting periods of my career -- all of the things we've learned about heparan sulfate and the resources we've developed over the years have come together with a variety of experts across multiple institutions who were quick to collaborate and share ideas," the author said. "If there's a silver lining to this pandemic, I hope it's that the scientific community will continue to work rapidly together like this to address other problems."

https://www.cell.com/cell/fulltext/S0092-8674(20)31230-7

https://ucsdnews.ucsd.edu/pressrelease/covid-19-virus-uses-heparan-sulfate-to-get-inside-cells

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fsars-cov-2-infection_2&filter=22