COVID-19 Research: University Of California Study Shows That Heparan Sulfate Assists SARS-CoV-2 Coronavirus To Bind To ACE2 and Enter Human Host Cells
Source: COVID-19 Research Sep 16, 2020 3 years, 7 months, 1 week, 2 days, 21 hours, 54 minutes ago
COVID-19 Research: Scientists from the University of California San Diego School of Medicine have found that the SARS-CoV-2 coronavirus needs a carbohydrate compound called heparin sulfate which is also found on lung cell surfaces and acts as a co-receptor for viral entry as it facilitates binding to te ACE2 receptors.
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The study team said that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin converting enzyme 2 (ACE2) through its Receptor Binding Domain (RBD).
Previous docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2 binding site. Both ACE2 and heparin can bind independently to spike protein in vitro and a ternary complex can be generated using heparin as a scaffold.
Electron micrographs of spike protein suggest that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. The team said that viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2.
The study findings were published in the peer-reviewed journal: Cell
https://www.cell.com/cell/pdf/S0092-8674(20)31230-7.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420312307%3Fshowall%3Dtrue
Lead researcher Dr Jeffrey Esko, PhD, Distinguished Professor of Cellular and Molecular Medicine and Co-Director of the Glycobiology Research and Training Center, University of California San Diego said, “ACE2 is only part of the story. It isn't the whole picture."
The study 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:
-First by removing heparan sulfate with enzymes
-Secondly by utilizing heparin as bait to lure and bind the coronavirus away from human cells.
As 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 researchers have long studied heparan sulfate and the role it plays in health and disease. Dr Esko led this study with visiting scholar Dr Thomas Mandel Clausen, PhD, and postdoctoral researcher Dr Daniel Sandoval, PhD.
Although Dr Esko's lab does not necessarily focus on viruses, Dr Clausen had previously studied how the malaria parasite interacts with a related carbohydrate on human cells and Dr Sandoval had been interested in viruses since he was an undergraduate student and keeps up with the latest virology research.
Sometime in March 2020, Dr Clausen perused the latest research coming out about SARS-CoV-2and came across a preliminary study that suggested an interaction between
the coronavirus's spike protein and another carbohydrate related to heparan sulfate and its possible role in ACE2 binding.
The study team began testing their theories in the lab. They discovered that the SARS-CoV-2 spike protein binds to heparin. The team also studied and found the exact part of the SARS-CoV-2 spike protein that interacts with heparin ie the receptor binding domain.
They found that when heparin is bound, the receptor-binding domain opens up and increases binding to ACE2. The SARS-CoV-2 coronavirus, 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.
Having this viral entry mechanism established the study team 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.
Significantly 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 ie the part responsible for preventing blood clots.
The study findings are still far from translating into a COVID-19 treatment for individuals, said Dr Esko. Researchers will need to test heparin and heparan sulfate inhibitors in animal models of SARS-CoV-2 infection.
Interestingly in another related study, University of California-San Diego 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.
The team concluded that manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities to treat COVID-19.
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