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Molecule May Offer New Potential Treatment Option for Resistant Ocular HSV

FEB 20, 2018 | KRISTI ROSA
It is estimated that about 50,000 new and recurring cases of ocular herpes simplex virus are diagnosed each year in the United States.

There are only about a handful of drugs that are currently available to treat herpes simplex-1 virus (HSV-1) infections of the eye, but these viruses are becoming increasingly resistant to what is available. Although scarred corneas can be replaced via transplant, past infection can make the eye more likely to reject the new tissue. If this happens, there’s not much else that can be done; without new treatments to overcome this, these patients will essentially go blind.

But a discovery made by investigators from the University of Illinois at Chicago may offer hope in the form of a small drug molecule called BX795. The molecule may offer an additional treatment for HSV-1 as new research shows that it is capable of eliminating the virus from cells within an individual’s cornea, according to a press release on the research.

“We were investigating a role for TBK-1 in HSV-1 lifecycle, and as an experiment, we tested its commercially available small molecule inhibitor, BX795,” senior author of the study Deepak Shukla, the Marion Schenk Professor of Ophthalmology and professor of microbiology and immunology at the UIC College of Medicine told Contagion®. “TBK-1 is a host kinase associated with cell's natural antiviral response, so we had hoped that by blocking this molecule via BX795 we will allow for better HSV-1 growth. To our surprise we saw the opposite—infection was completely suppressed.”

One of the primary treatment options available for ocular herpes is acyclovir (ACV) and its analogs. “ACV, valacyclovir, and famciclovir are usually administered systemically, and trifluridine and ganciclovir gel are administered topically,” the study authors write. There are limitations to these drugs though, “as nucleoside analogs rely on blocking viral DNA duplication and do not act directly to prevent viral protein synthesis.” As such, there are frequent reports of drug resistance. In addition, it is known that trifluridine, when used for a prolonged period of time, can actually cause ocular disorders; prolonged use of ACV can result in nephrotoxicity.

BX795 operates differently; instead of preventing the virus from creating the proteins it needs to reproduce, BX795 works within the host cells to help them clear the virus.

“In our hands, we found that this compound inhibits phosphorylation of a host (cell) molecule (Akt). Phosphorylation of Akt is needed for viral protein synthesis,” Shukla explained. “So, in essence, BX795 blocks viral protein synthesis while the currently available drugs (such as acyclovir) block viral DNA synthesis. As you can see, it represents an entirely new class of antivirals against HSV: different target and totally different mode of action.”

Shukla and his team found that BX795 was able to clear HSV-1 in all of the following: cultured human corneal cells, donated human corneas, and the corneas of HSV-1 infected mice.

Two additional key takeaways that make the molecule look even more promising as a potential future treatment for HSV-1 are that it did not take very high concentrations to successfully eliminate the virus, “without any detectable toxic effects,” Shukla said.

Thus far, Shukla and his team have tested the molecule in the form of a topically administered eye drop. However, the researchers aren’t stopping there. “We are testing new formulations and performing further experiments to develop this compound for topical (eye drop, ointment) as well as systemic usages (oral pills and injectable),” Shukla said.

The research team hopes to take the study a step further to apply this molecule as treatment for other viral infections.

“In our hands, we are seeing evidence that it blocks genital herpes virus infection with equal potency as HSV-1,” Shukla said. “Since it targets a host molecule, which is needed by many common viruses for their own protein synthesis, in the future we hope to demonstrate its broad spectrum antiviral usages against HPV, HIV and many other viruses.”
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