SARS-CoV-2 is the virus that causes COVID-19, and it uses surface spike proteins to latch onto human cells to initiate infections; this report suggests that the blood thinner heparin which is also available in non-anticoagulant varieties binds tightly with the surface spike protein which can potentially block the infection from happening.
The researchers suggest that this drug may be an ideal decoy that could be introduced into the body using a nasal spray or a nebulizer to run interference with the virus to lower the odds of infection. Similar decoy type strategies have already been shown to have promise in curbing other viruses such as dengue, Zika, and influenza A.
“This approach could be used as an early intervention to reduce the infection among people who have tested positive, but aren’t yet suffering symptoms. But we also see this as part of a larger antiviral strategy,” said Robert Linhardt, lead author and a professor of chemistry and chemical biology at Rensselaer Polytechnic Institute. “Ultimately, we want a vaccine, but there are many ways to combat a virus, and as we’ve seen with HIV, with the right combination of therapies, we can control the disease until a vaccine is found.”
In order to infect a cell the virus must first latch onto a specific target on the cell surface, then it must slice through the cell membrane and insert its own genetic instructions into the cell to hijack the cellular machinery within it to produce replicas of itself.
The idea is that the virus could just as easily be persuaded to lock onto a decoy molecule that offers the same fit as the cellular target, and once bound to this decoy the virus would become neutralized and unable to infect a cell or free itself eventually degrading.
SARS-CoV-2 binds to an ACE2 receptor in humans, heparin was hypothesized to offer an equally attractive target, and in a binding essay it was found to bind to the same trimeric SARS-CoV-2 spike protein at 73 picomoles, which is a measure of the interaction between the two molecules.
“That’s exceptional, extremely tight binding,” said Jonathan Dordick, a chemical and biological engineering professor at Rensselaer who is collaborating with Linhardt to develop the decoy strategy. “It’s hundreds of thousands of times tighter than a typical antibody antigen. Once it binds, it’s not going to come off.”
In reviewing sequencing data for SARS-CoV-2 the team recognized certain motifs on the spike protein that were strongly suspected to bind to heparin. The team also tested how strongly three heparin variants binded to SARS-CoV-2 using computational modeling to determine specific sites where the compounds bind to the virus; results all confirmed that heparin is a promising candidate for the decoy strategy, and subsequently the team has initiated work on assessment of antiviral activity and cytotoxicity in mammalian cells.
“This isn’t the only virus that we’re going to confront in a pandemic,” Dordick said. “We don’t really have great antivirals, but this is a pathway forward. We need to be in a position where we understand how things like heparin and related compounds can block virus entry.”
The decoy strategy was previously demonstrated on viruses with mechanisms similar to SARS-CoV-2: A trap was created for dengue virus by attaching specific aptamers to tips and vertices of a five pointed star made of folded DNA, floating in the bloodstream the trap lights up when sprung to create the world’s most sensitive test for the mosquitoes borne disease. Before that a synthetic polymer was configured to match sialic acid latch points on influenza virus to reduce the influenza A mortality rate in mice from 100% to 25% over 14 days.
“This innovative approach to effectively trapping virusus is a prime example of how biotechnology approaches developed at Rensselaer are being brought forward to address challenging global health problems,” said Deepak Vashishth, the director of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer, of which both Dordick and Linhardt are a part. “Professors Dordick and Linhardt have worked collaboratively across disciplines, and their research shows promise even beyond this current pandemic.“
“Characterization of glycosaminoglycan and novel coronavirus (SARS-CoV-2) spike glycoprotein binding interactions” was published in Antiviral Research. At Rensselaer, Linhardt and Dordick were joined in the research by Fuming Zhang, and also by researchers at the University of California San Diego, Duke University, and the University of George, Athens with support from the National Institutes of Health.
