Convincing research indicates that heparin may protect against COVID-19

A compelling new study conducted by an international team of researchers has shown that the widely used anticoagulant heparin causes coronavirus disease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 (new coronavirus infection) has been shown to be able to prevent the infection of (#, if there is no character limit, add brackets when first appearing).

Jeffrey Esko (University of California San Diego) and colleagues not only require the host cell receptor angiotensin-converting enzyme 2 (ACE2) for virus binding and entry, but SARS-CoV-2 also depends on cellular heparan sulfate. I showed that.

They also showed that the anticoagulants heparin and heparin lyase, as well as the anticoagulant heparin, all potently block SARS-CoV-2 binding. Spike protein Prevents viral infection of human host cells.

The spike protein is a viral membrane structure used by SARS-CoV-2 to attach to host cell ACE2 early in the infection process.

Currently, heparan sulfate also seems to be required for this spike protein binding, says Esko and the team.

“These findings support a model of SARS-CoV-2 infection, where viral attachment and infection involves the formation of a complex between heparan sulfate and ACE2,” the researchers say. “Manipulation of heparan sulfate or inhibition of viral attachment by exogenous heparin may represent new therapeutic opportunities.”

A preprinted version of the paper is available on the server bioRxiv*, The paper is undergoing peer review.

Molecular modeling of the interaction of SARS-CoV-2 spiked RBD with heparin. A, Molecular model of SARS CoV-2 S protein trimer (PDB: 6VSB and 6M0J) rendered in Pymol. ACE2 is shown in blue and RBD is shown in green with an open structure. The set of positively charged residues is distal to the ACE2 binding site. B, Electrostatic surface rendering of SARS-CoV-2 RBD (PDB:6M17) docked with dp4 heparin oligosaccharides. Blue and red surfaces indicate electropositive and electronegative surfaces, respectively. Oligosaccharides are represented using standard CPK format. Mesh surface rendering of C, dp4 heparin oligosaccharide (red) and docked RBD (green).

The search for alternative approaches to vaccines

Since the outbreak of COVID-19 began in Wuhan, China at the end of last year, the pandemic has now infected more than 13.7 million people and caused more than 588,000 deaths.

While many countries are taking social distance and isolation measures to control the spread of COVID-19, researchers around the world are competing for the development of antiviral drugs and vaccines. However, so far only one antiviral agent (lemdecibir) has been approved for use with COVID-19, and the vaccine may not be available for at least a year.

“Understanding the mechanism of SARS-CoV-2 infection and its tissue tropism could reveal that other targets interfere with and spread the viral infection,” Esko and colleagues said.

Glico calix

The glycocalyx, or pericellular matrix, is a complex network of glycans and glycoconjugates that all viruses must first contact and penetrate before they can bind to cell membrane receptors and mediate viral entry.

Many viruses use glycans as adhesins that promote early host cell binding, such as influenza virus and HIV. Coronavirus..

Some viruses interact with heparan sulfate (HS). It is a highly negatively charged polysaccharide found on some membrane or extracellular matrix proteoglycans.

“HS has different structures depending on cell type and tissue, as well as sex and age. Therefore, HS may contribute to tissue tropism and susceptibility of various patient populations in addition to ACE2 expression level. The team suggests.

Heparan sulfate was required for SARS-CoV-2 attachment

Now Esko et al. provide compelling new evidence that HS is required for SARS-CoV-2 host cell attachment.

Docking studies suggest that spike proteins attach to the heparin/heparan sulfate binding site via a docking site composed of positively charged amino acid residues within the RBD subdomain adjacent to the ACE2-binding domain Did.

The team says that in vitro, cell binding of the ectodomain of the SARS-CoV-2 spike protein requires binding to both HS and ACE2, suggesting that HS functions as a coreceptor. I am.

Enzymatic removal of HS, genetic studies, and heparin/HS competition studies all depend on whether spike proteins were introduced as recombinant proteins. Fake virus Or native SARS-CoV-2 virions attached to host cells HS in a manner that coordinated with ACE2 binding.

“This data provides important insights into the pathogenic mechanism of SARS-CoV-2 infection and suggests the HS spike protein complex as a new therapeutic target to prevent infection,” the authors write. ..

Heparin treatment blocked spike binding and SARS-CoV-2 infection

In fact, researchers found that therapeutic unfractionated heparin, non-anticoagulant heparin, and heparin lyase (which degrades HS) all strongly blocked spike binding, spiking pseudoviruses and native SARS-CoV. -We found that we prevented infection by both.

“This study reveals HS as a novel receptor for SARS-CoV-2, and could use HS mimetics, HS-degrading lyases, and metabolic inhibitors of HS biosynthesis to develop therapeutics to combat COVID-19. Suggests gender,” the team concludes. ..

*Important Notices

bioRxiv It publishes preliminary non-peer reviewed scientific reports and should not be considered conclusive and should not guide clinical practice/health-related behaviors or be treated as established information.