Researchers have developed a molecule that effectively inhibits an enzyme instrumental in spreading the herpes simplex virus in humans. They say their discovery could lead to a new treatment for herpes simplex infections and other viruses, as well as diseases that rely on this enzyme to spread, such as cancer.
Many adults are infected with herpes simplex virus type 1 (HSV-1), a lifelong condition that often manifests as annoying cold sores but has the potential, albeit rare, to lead to more serious brain or eye infections. Previous studies have presented evidence implicating the enzyme heparanase (HPSE) in the spread of HSV-1, other viruses, and cancer.
Heparan sulfate is present in the extracellular matrix (ECM) of every tissue and on the surface of pretty much every cell and is responsible for regulating cell to cell interactions and maintaining the health of the ECM. The only known enzyme capable of breaking down – or cleaving – heparan sulfate is HPSE. Normally, it does so in a controlled way, freeing molecules needed for biological processes elsewhere in the body. But heparan sulfate also plays a role in the cell entry and release of many viruses, including HSV-1, and the overexpression of HPSE and uncontrolled cleavage of heparan sulfate can result in abnormal cell activation and significant tissue damage.
Because of its role in assisting the spread of viruses and cancer, research has been focused on developing a means of inhibiting HPSE. Now, researchers led by the University of Illinois Chicago have identified a molecule that inhibits the spread of HSV-1, bringing us closer to an effective treatment against viruses and cancer.
“We showed the inhibitor working against the herpes virus, but it has the potential to be used in all kinds of diseases,” said Deepak Shukla, a corresponding author of the study.
In a previous study, the researchers identified how HSV-1 modulated the synthesis of heparan sulfate to optimize infection and virus spread. In the current study, they designed and synthesized different saccharides and evaluated their ability to inhibit HPSE activity. Saccharides are the building units of carbohydrates that are classified by the number of monomers that comprise them. For example, combining two monosaccharides (simple sugars) creates a disaccharide, whereas oligosaccharides contain two to 10 simple sugars.
Because HSV-1 can cause ocular herpes or herpes keratitis, an infection of the eye’s cornea, the researchers tested their various saccharides on human corneal epithelial cells infected with the virus. Administering the compounds before or at the same time as infection with HSV-1, they found that treatment with the hexa- and octasaccharides produced substantial reductions in the amount of extracellular virus in the samples and inhibited viral spread.
Examining the cells treated with these saccharides, the researchers observed substantially higher levels of surface heparan sulfate, similar to non-HSV-1-infected cells. They also found that the cells exhibited a significant increase in migration, indicating improved wound healing abilities that the researchers attributed to the antiviral activity of the hexa- and octasaccharides.
From their findings, the researchers concluded that the saccharide compounds had a dual mode of action, impeding the virus’ entry to the cells as well as its release.
Because HPSE plays a role in the pro-survival activity of cells, previous attempts to develop an HPSE inhibitor have run into issues with toxicity. Here, the researchers found no evidence that the effective compounds were toxic to the corneal cells. Additionally, HPSE inhibitors are often a form of the drug heparin, which is used to prevent blood clotting, so they can cause bleeding. As the hexa- and octasaccharides used by the researchers don’t contain the disaccharide unit critical for activating heparin’s anticoagulant activity, bleeding was not a problem.
“Inhibition of HPSE in corneal cells is important for wound healing and modulation of ocular inflammation,” said the researchers. “Collectively, these observations demonstrate that HPSE inhibitors can prevent viral release and subsequent spread to other cells and tissues.”
The researchers say there’s still work to be done before their HPSE inhibitor is ready for clinical use. Nonetheless, it’s an important step towards developing a novel treatment for HSV-1, other viruses and cancer.
The study was published in the journal Angewandte Chemie.
Source: University of Illinois Chicago
