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February 27, 2018
Molecule halts herpes of the eye
At a Glance
- Scientists identified a small molecule that prevents herpes simplex-1 virus from making viral proteins in human cornea cell lines and mouse models of ocular herpes.
- The findings suggest a new class of molecule that may be useful for developing antiviral treatments.
Herpes of the eye, or ocular herpes, is a recurring viral infection that’s usually caused by the herpes simplex virus-1 (HSV-1). This is the same virus that causes cold sores. Ocular herpes can also be caused by herpes simplex virus-2, which is the main cause of genital herpes.
Ocular herpes can produce sores on the eyelid or surface of the cornea. Recurrences can lead to complications like blindness or meningoencephalitis, a lethal infection of the brain. There’s no cure for ocular herpes, but it can be controlled with antiviral drugs.
The main class of antiviral drugs used to treat ocular herpes blocks the virus’ ability to replicate (make copies of itself). The drugs are nucleoside analogs, which look similar to DNA nucleotides but have a modification that interferes with DNA replication. Some people have viruses that develop resistance to these antivirals and would benefit from other types of treatments.
A team led by Dr. Deepak Shukla of the University of Illinois at Chicago investigated the antiviral properties of a molecule called BX795 in cell lines and mouse models of ocular herpes. The research was supported by NIH’s National Eye Institute (NEI). Results were published in Science Translational Medicine on February 14, 2018.
The researchers were initially testing BX795 in cells infected with HSV-1 to better understand aspects of the host cells’ defense system. BX795 is known to block a molecule called TANK-binding kinase 1 (TBK1), which cells produce to protect themselves after an infection. The scientists expected that blocking this molecule would increase the amount of virus in the cell. They were surprised to find that the drug reduced herpes infections.
The team compared BX795 with an antiviral currently prescribed for herpes, called TFT (trifluridine or trifluorothymidine), in a human corneal epithelial cell line infected with HSV-1. They found that both treatments reduced HSV-1 infections in the cells to a similar degree. They saw similar results when they compared the two drugs in a mouse model of ocular herpes.
When BX795 and TFT were applied to human corneal epithelial cells together, they did not show synergistic effects. The researchers also compared BX795 with several other herpes antivirals, including acyclovir, famciclovir, ganciclovir, and penciclovir. BX795 was similar or better at suppressing herpes infections in human corneal epithelial cells than any of the other antivirals—and at lower doses.
Using protein and gene analysis, the team discovered that BX795 works by blocking viral protein synthesis through Akt, a host cell molecule required to start protein synthesis. BX795 also reduced HSV-1 protein levels in primary human corneal cells and human cornea buttons that the researchers secured from tissue banks.
“We have needed alternative drugs that work on new targets for a very long time because patients who develop resistance to nucleoside analogs have very few good options for treating their infection,” Shukla says. “We have found a molecule that works in a totally novel fashion. Instead of working on the virus, it works in the host cells and helps them to clear the virus.”
Given that BX795 targets a common viral replication process, it may be useful against other viruses as well. However, more studies are needed to determine its effects on other viruses and to understand its effects in people.
—by Tianna Hicklin, Ph.D.
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References: An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye. Jaishankar D, Yakoub AM, Yadavalli T, Agelidis A, Thakkar N, Hadigal S, Ames J, Shukla D. Sci Transl Med. 2018 Feb 14;10(428). pii: eaan5861. doi: 10.1126/scitranslmed.aan5861. PMID: 29444978.
Funding: NIH’s National Eye Institute (NEI).