Researchers have developed a molecule that effectively inhibits an enzyme that spreads the herpes simplex virus in humans. They say their findings could lead to new treatments 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 disease that usually manifests itself as annoying cold sores but can also lead to more serious brain or eye infections, although this is rare. Previous studies have presented evidence that hepatoglycanase (HPSE) is involved in the transmission of HSV-1, other viruses, and cancer.
Heparin sulfate is found in the extracellular matrix (ECM) of every tissue and on the surface of nearly every cell, where it is responsible for regulating cell-cell interactions and maintaining the health of the ECM. The only enzyme known to break down or cleave heparin sulfate is HPSE. Normally, it breaks down in a controlled manner, releasing molecules needed for biological processes elsewhere in the body. However, heparin sulfate also plays a role in the cellular entry and release of many viruses, including HSV-1, and overexpression of HPSE and uncontrolled heparin sulfate cleavage can lead to abnormal cell activation and severe tissue damage.
Because of HPSE's role in assisting the spread of viruses and cancer, researchers have been working to develop a way to inhibit HPSE. Now, researchers led by the University of Illinois at Chicago have discovered a molecule that inhibits the spread of HSV-1, bringing us one step closer to effective treatments for the virus and cancer.
"We showed this inhibitor works against herpes viruses, but it has the potential to be used in a variety of diseases," said Deepak Shukla, corresponding author of the study.
In a previous study, the researchers determined how HSV-1 regulates heparin sulfate synthesis to optimize infection and viral spread. In the current study, they designed and synthesized different sugars and evaluated their ability to inhibit HPSE activity. Sugars are the building blocks of carbohydrates and are classified according to the number of monomers they are composed of. For example, two monosaccharides (monosaccharides) join together to form a disaccharide, while oligosaccharides contain between 2 and 10 monosaccharides.
Because HSV-1 can cause ocular herpes or herpetic keratitis, an infection of the cornea of the eye, the researchers tested various sugars on human corneal epithelial cells infected with the virus. Giving these compounds before or at the same time as infection with HSV-1, they found that the amount of extracellular virus in the samples was significantly reduced and viral spread was inhibited after treatment with hexasaccharides and octasaccharides.
When examining cells treated with these sugars, the researchers observed significantly increased levels of surface heparin sulfate, similar to those in cells not infected with HSV-1. The researchers also found that the cells' ability to migrate was significantly enhanced, indicating improved wound healing, which the researchers believe is due to the antiviral activity of the hexasaccharides and octasaccharides.
Based on the findings, the researchers concluded that these sugar compounds have a dual mode of action, blocking viral entry into cells and blocking viral release.
Due to HPSE's role in activities that promote cell survival, previous attempts to develop HPSE inhibitors have encountered toxicity issues. Here, the researchers found no evidence that the active compounds were toxic to corneal cells. In addition, HPSE inhibitors are usually heparin-based drugs used to prevent blood clotting and therefore may cause bleeding. Because the hexasaccharides and octasaccharides used by the researchers do not contain the disaccharide units that are critical for activating heparin's anticoagulant activity, bleeding was not an issue.
"Inhibition of HPSE in corneal cells is important for wound healing and regulating ocular inflammation. Taken together, these observations suggest that HPSE inhibitors may prevent viral release and subsequent spread to other cells and tissues," the researchers said.
The researchers say there is still much work to be done before their HPSE inhibitor is ready for clinical use. Still, it's an important step toward developing new treatments for HSV-1, other viruses, and cancer.
The research was published in the journal AngewandteChemie.