Coronavirus Uses Heparan Sulfate to Get Inside Cells

Coronavirus

New research from the University of California and the University of Copenhagen into COVID-19 redefines the known mechanism of infection of human cells, highlighting a new target for simple therapeutic intervention using heparin anti-coagulants.

Coronavirus

The coronavirus pandemic is far from over and researchers all over the world are trying to get new insights about the virus to help stop the spread or mitigate the disease impact. Now, an international team of researchers, led from the University of California has uncovered a new way to possibly fight the virus.

A small group of Danish researchers at Copenhagen Center for Glycomics at the Department for Cellular and Molecular Medicine at the University of Copenhagen has helped their American researcher colleagues discover that the Coronavirus uses special sugars known as heparan sulfates for infection of human cells.

The finding has direct implications for potential therapeutic intervention strategies with use of heparan sulfate derivatives, such as the widely used anti-coagulant heparin and its derivatives, for inhibition of virus infection.

‘Our discovery of heparin sulfate as a required co-receptor for infection, opens a whole new field for the development of therapy. Namely, there are many ways in which we can target the interaction directly, possibly preventing the virus ability to infect the human cells. This can be done by competing with similar glycans, such as Heparin, or by modulating the presentation of the heparan sulfate on the host cell’, says Thomas Mandel Clausen, the first author to the study. He is both a visiting scholar at the University of California and an Associate Professor at the University of Copenhagen.

No heparan sulfates, no infection

Heparan sulfates are a class of long polysaccharides with characteristic sulfation patterns that serve in many biological interactions including as receptor for several viruses. The SARS-CoV-2 spike protein that mediates the first essential step in infection of human cells was known to bind the human ACE2 protein to attach to and infect cells, however, the new study from the research team now shows that this binding requires heparan sulfate as a co-receptor.

SARS-CoV-2 infection of human cells expressing ACE2 was inhibited by heparin, and when human cells expressing ACE2 were genetically engineered to lack the capacity to produce heparan sulfates they were no longer infected.

Thomas Mandel Clausen and co-first author Daniel Sandoval to the study had the original research idea and did the research under the supervision of the world-leader in glycosaminoglycan research, professor Jeffrey D. Esko. Their team is already involved in the screening and optimal design of heparin sugar inhibitors to treat SARS-CoV-2 infection.

‘The results are promising so we are optimistic. Many of these compounds are already clinically approved for other indications and could therefore quickly be repurposed for Covid-19 treatment’, adds Thomas Mandel Clausen

One of the most widely used drug in medicine

Co-author and assistant professor Zhang Yang at Copenhagen Center for Glycomics, who contributed to the study explains: “Many viruses including the seasonal influenza and earlier SARS and MERS viruses use glycans as receptors for binding to human cells and infection, and we were convinced that the SARS-CoV-2 spike protein was no different. While several preprint reports were suggesting that this could be the case, I am really happy that we were able to combine many resources and efforts in a very short time and provide conclusive evidence.”

Heparin is one of the most used drugs in medicine today, where its anti-coagulative properties are used primarily to prevent blood clotting. Heparin is a highly sulfated version of heparan sulfate and the active components are 5-6 sugars with sulfate groups.

The anti-coagulant properties of Heparin may limit its use for Covid-19 treatment in patients, however the team showed that heparin derivatives in which the anti-coagulative properties have been removed were equally as potent in inhibiting infection. Heparin and derivatives can be made synthetically as small homogenous sugars and the researchers envision that optimal design of candidate compounds will be needed to develop useful inhibitors for SARS-CoV-2.

What science should be

‘We have worked around the clock the past 6 months with special permissions for covid-19 work. I am confident that small molecule inhibitors based on heparan sulfates or heparin can be developed into simple and useful drugs for preventing and alleviating infections soon. A similar strategy was used in the development of inhibitors of the seasonal influenza, such as Tamiflu, that are small molecule sugar inhibitors that blocks the adhesion-release process by which Influenza infection works’, says Daniel Sandoval, who is co-first author on the study.

‘This work has been a very unique experience. The consequences of Covid-19 have been terrible, especially here in California where we work. I am proud and humbled by having had the opportunity to work with such an amazing talented group of people from many backgrounds that all selflessly came together with a common goal of fighting the pandemic. This is truly what science should be’, says Thomas Mandel Clausen to finish.

The study was prepublished in Cell September 14 and will appear in the early issue in November. The studies were partly funded from Denmark by the Benzon foundation and the Danish National Research Foundation.

Read the entire study: “SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2”

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