COVID-19 Resource Center
COVID-19 Resource Center
Source/Disclosures
Disclosures: Dordick reports no relevant financial disclosures.
August 28, 2020
5 min read
Save

Heparin may neutralize virus that causes COVID-19

Source/Disclosures
Disclosures: Dordick reports no relevant financial disclosures.
You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

The COVID-19 pandemic has prompted a flurry of scientific studies of various potential treatments and vaccines for the novel coronavirus.

One such study, conducted by researchers at Rensselaer Polytechnic Institute and published in Antiviral Research, showed the FDA-approved anticoagulant heparin may neutralize SARS-CoV-2, the virus that causes COVID-19.

Jonathan S. Dordick, PhD, the Howard P. Isermann Professor of Chemical and Biological Engineering at Rensselaer Polytechnic Institute

SARS-CoV-2 uses a surface spike protein to attach to human cells and infect them, according to the study background. However, because heparin binds tightly with the surface spike protein, it potentially could serve as a decoy and prevent infection from occurring.

“We’ve known for quite some time that heparin possesses the ability to be antiviral; it has the ability to bind to very specific proteins on the surfaces of viruses,” Jonathan S. Dordick, PhD, the Howard P. Isermann Professor of Chemical and Biological Engineering at Rensselaer and one of the study authors, said in an interview with Healio. “So that wasn’t really a surprise. The other reason we studied heparin had nothing to do with its antiviral properties.”

Dordick spoke with Healio about the study, his reasons for pursuing heparin as a potential COVID-19 treatment, and the potential of this common blood thinner to neutralize the coronavirus.

Question: What inspired you to study heparin for COVID-19?

Answer: We noticed, through some of our collaborations with medical centers, that COVID-19 was causing some patients to experience what appeared to be significant microthrombosis. So, we talked to medical centers about putting people on heparin when they come to the hospital, whether it’s subcutaneous low-molecular-weight heparin or unfractionated heparin. A number of papers that came out subsequently indicated that, indeed, anticoagulation therapy improved the outcome of patients, particularly those who were seriously ill.

Meanwhile, we started exploring whether heparin has the ability to bind to various viral proteins, particularly the spike protein. We looked at the binding and then sought to understand the mechanism through which that happens.

We have another paper published in Cell Discovery that deals with the measurement of the antiviral activity that prevents the virus from infecting the cell. We took some relatively simple studies that we were doing with heparin and some other molecules, and we applied them to see if heparin would bind to the virus. We aren’t using the live virus in this study because that requires specialized facilities. However, we did measure the binding to the spike protein, and it was exceptionally strong.

Q: What did you learn from this?

A: This got us thinking about heparin analogues, as well. We wondered how tight the binding was with analogues. We were very surprised when we noticed that the binding was about a thousand times stronger than that of most antibodies. Does it really matter? Probably not that much, but it means it’s basically irreversible.

The concept was similar to our other investigations looking at a decoy approach. We knew that the virus spike protein would bind to the cell surface, and specifically the human ACE2 receptor. However, it’s guided into the ACE2 receptor by being able to interact with the glycosaminoglycans (primarily heparan sulfate) that are on the surface of various human cells. We thought maybe we could intercept this spike protein-heparan sulfate interaction via a decoy approach where we add heparin. Would it simply interfere with or hijack the binding of the virus to the cell surface? And, would this result in neutralization of the virus? That’s very similar to how neutralizing antibodies function, where the antibodies bind to the spike protein and prevents that protein from interacting with the ACE2 receptor. We thought that for this to be demonstrable, we had to show that it binds to the spike protein and show how well it binds.

Q: Were you able to demonstrate that?

A: Yes, we showed quantitatively that it bound very tightly to the spike protein. Then, we did some modeling studies to get an idea of where it bound on the spike protein. This paper does not go into the activity in neutralizing the virus, but in our follow-up work published in Cell Discovery, we showed that it does, in fact, inhibit the virus from infecting cells.

Heparin is a large polysaccharide, so it will wrap itself around the spike protein. Once it does that, the virus ultimately disintegrates; if a virus can’t infect a cell, it doesn’t have a very long lifetime.

We didn’t just study this with heparin. We are developing a nonanimal source heparin as a biosynthetic. Some of the nonanticoagulant intermediates leading up to our biosynthetic heparin that showed activity that was nearly the same as natural heparin. That told us the larger size and the degree of sulfation on the heparin play a major role in binding to the spike protein. What makes this even more exciting is that heparin is extremely safe. Physicians have known how to use it for a long time, and they know how to use it quite well.

We are now looking at other ways we might be able to use heparin, such as in an inhalation version. Another possibility is to use it as a nasal spray. Several papers show that the infection first takes hold in the nasal passages.

Q: How might heparin shortages impact the ability to use the drug for COVID-19?

A: This is a big problem. Heparin comes from pig intestine. Asian swine flu has wiped out large numbers of pigs in China, and China is the biggest supplier of heparin. Additionally, there is concern about the safety of these animal-based products. Only in the last step of its production does heparin go through a pharmaceutical process; everything before that is basically in an unregulated environment. That is why about a decade ago we decided to develop a biosynthetic heparin that effectively has the properties of heparin but uses a highly controlled synthesis, like a true pharmaceutical.

There have been shortages of heparin for quite some time. It’s an important drug that’s used in many different surgeries and in dialysis. I don’t know that it’s a concern right now in COVID-19, but the fact that these shortages occur periodically makes it a concern. If we were to use it in a nasal spray, however, the amount we would need would be so small that it would not detract from the use of heparin in surgeries.

Q: What is the take-home message of your study?

A: This is one of several examples of work underway showing that existing drugs can play a major role in treating and preventing the spread of the coronavirus. I would imagine many other viruses would be subject to something similar. In fact, the reason we have heparin in our intestines and other organs is likely for anti-infective purposes. It’s not an anticoagulant in our bodies but may be as effective as an antiparasitic. For example, if you think about it in this way, heparin already has the natural function of preventing infection.

References:

For more information:

Jonathan S. Dordick, PhD, can be reached at Rensselaer Polytechnic Institute Center for Biotechnology and Interdisciplinary Studies, Room 4211, 110 8th St., Troy, NY 12180-3590; email: dordick@rpi.edu.