Eyeworld

18 April 2018 EW NEWS & OPINION by Liz Hillman EyeWorld Staff Writer and topical trifluridine and ganciclo- vir) as well. Jaishankar et al. wrote in the research published in Science Translational Medicine that "dose analysis experiments demonstrated that fivefold higher concentrations of nucleoside analogs were required to achieve a similar antiviral efficacy to BX795 at 10 mm." 1 Famciclovir, the study authors noted, did not reach the same efficacy as BX795 even at 50 mm. It also showed promise against HSV-1 strains that had developed drug resistance. "Unlike nucleoside analogs, the antiviral activity of BX795 was also strong against an ACV-resistant strain, HSV-1 (KOS)tk12. … Togeth- er, these data suggest that BX795 treatment achieves higher efficacy at a lower dose than existing anti-her- pes virus therapies and it could be effectively used against an ACV-re- sistant strain as well," Jaishankar et al. wrote. So how is a drug that was initial- ly meant to enhance the viruses' infectious ability doing the exact opposite? Dr. Shukla explained that further research led them to find that it blocks viral protein synthesis by acting on a host protein that was required by the virus to perform this synthesis. "BX795 blocks phosphorylation of Akt [protein kinase B], which results in a loss of viral protein syn- thesis," he said. "The most exciting part is, conceptually, if we block this host protein, we can completely block viral protein synthesis; this is most likely not going to be specific to HSV-1. We have already tested it with genital herpes [HSV-2], and it blocks genital herpes very well. A bunch of other viruses, HIV, hu- man papilloma virus, adeno viruses [such as conjunctivitis], all seem to use this host protein for their own synthesis. A broad-spectrum anti- viral could be generated out of this discovery." Unlike current antivirals, Dr. Shukla said this research established a new class of antivirals in BX795. Nucleoside analogs, for example, in- hibit viral DNA synthesis, but BX795 inhibits viral protein synthesis, which Dr. Shukla said can act before and after DNA synthesis. The researchers also evaluated toxicity. The drug did not show tox- icity in human corneal endothelial interferon … which is bad for the vi- rus," Dr. Shukla said. "We had hoped that once you inhibit TBK1 [with BX795] … that the virus should have a better time growing in these cells, inhibited by the inhibitor." When this didn't happen, Dr. Shukla and his team began testing different models of infection: cor- neal epithelial cells, organ cultures using human corneas, and animal models of corneal infection. In all three cases, they found BX795 inhibited HSV-1 infection. What's more, the researchers compared the effect of HSV-1 infection with com- monly prescribed nucleoside analogs (acyclovir, valacyclovir, famciclovir, "It was not meant to be tested as an antiviral," Dr. Shukla said of BX795. "It just happened to turn into an antiviral, so that was the surprising part." Giving some history to the research, Dr. Shukla said he was interested in learning about the role of autophagy (the host cells' own re- cycling mechanism) and HSV-1. Her- pes, Dr. Shukla said, takes control of host cells' autophagy, and in the initial experiment, TBK1 inhibition with BX795 was important because it is involved with the host's innate immunity and control of autophagy. "The virus tries to suppress TBK1 because it leads to production of New drug acts on host protein to block viral protein synthesis D eepak Shukla, PhD, and his team did not set out to discover a new class of antiviral drugs that could change how a wide range of viruses are treated in the future. Instead, he and his team sought to learn more about the mechanism of herpes simplex virus type 1 (HSV- 1) by actually trying to enhance infections. Treating human corneal epithe- lial cells infected with HSV-1 with the compound BX795, a TANK-bind- ing kinase 1 (TBK1) inhibitor, Dr. Shukla, Marion H. Schenk Esq. Pro- fessor in Ophthalmology, professor of microbiology and immunology, University of Illinois at Chicago, and his team expected to see enhanced virulence of HSV-1. Instead, they saw an anti-herpetic effect. The ex- periment was repeated several times with similar results. Ocular HSV research yields new class of antiviral drugs that could have broad reach Mouse eye infected with GFP-tagged HSV-1 Source: Carl Zeiss Meditec Research highlight " A broad-spectrum antiviral could be generated out of this discovery. " —Deepak Shukla, PhD

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