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Deepak Shukla, Dinesh Jaishankar; Targeting Akt phosphorylation by a small molecule inhibitor generates an effective strategy to curb corneal herpes simplex virus type-1 infection. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4931.
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Herpes simplex virus type-1 (HSV-1) causes recurrent infections of the cornea that may advance to corneal blindness. Nucleoside analogs currently form the primary class of anti-herpetic drugs but are afflicted by the emergence of viral resistance. We demonstrate that targeting Akt phosphorylation by a small molecule inhibitor, BX795, can very effectively stop virus replication and corneal disease manifestations.
Multiple HSV-1 wild-type as well as recombinant strains were used including a dual color HSV-1 reproter virus that expresses early and late genes under GFP and RFP promoters respectively. Antiviral efficacy of BX795 was demonstrated in cultured human corneal epithelial (HCE) cells, organotypic cultures of the human cornea, and murine models of corneal HSV-1 infection using western analysis, plaque formation and flow-cytometry assays. Efficacy of BX795 was compared against FDA approved drugs such as acyclovir, ganciclovir, famciclovir, penciclovir, and trifluridine using quantitative flow cytometry and viral plaque assays. Mechanism behind the antiviral action of BX795 and its ability to target Akt phosphorylation was demonstrated in HCE cells using phospho-Akt antibodies and western analysis. Antiviral potential against an acyclovir-resistant strain was also demonstrated in HCE cells by plaque assay and western analysis of HSV-1 proteins.
Our in vitro, ex vivo and in vivo models of corneal infection demonstrate that BX795 is a potent inhibitor of HSV-1 growth in the cornea. It requires a lower concentration and shows similar or better antiviral efficacy than clinically approved drugs including acyclovir, ganciclovir, famciclovir, penciclovir, and trifluridine. We demonstrate that the antiviral action of BX795 originates from its previously unknown ability to target Akt phosphorylation. Since it is not a nucleoside analog, it also exhibits high potency against acyclovir-resistant strains.
Our studies describe a novel class of antiviral molecule that can provide an efficacious alternative therapy against corneal HSV-1 infection. Our findings are highly innovative and a part of this study is on its way for publication in Science Translational Medicine.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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