Developing novel molecular therapies for eye diseases has been identified as a high priority research goal by the National Eye Institute. Infection of the eye and more specifically, the cornea, by herpes simplex virus type-1 (HSV-1) results in epithelial or stromal keratitis and leads to severe inflammation, pain, corneal cloudiness and, in some cases, blindness. At present, this viral infection of the eye remains incurable and effective vaccines or prophylactic agents against HSV-1 do not exist. Many existing herpetic treatments including acyclovir fail to demonstrate high efficacy in the eye, and are therefore not commonly prescribed for controlling corneal infections. Emergence of drug resistance is also on the rise against acyclovir and similar nucleoside analogs that are currently used to control HSV-1 in general. This proposal will simultaneously test two alternate molecular therapies against HSV-1 using a murine model of corneal infection and examine their synergistic ability to control symptoms and reduce the spread of the virus in the eye and also to the trigeminal ganglion. The first therapy will originate from our hypothesis that high affinity inhibition of the interaction between HSV-1 envelope glycoprotein gD and its cognate receptors on the corneal cell surface can generate strong prophylactic as well as therapeutic effects. To prove our hypothesis we will test an RNA aptamer that binds to gD with nanomolar affinity and blocks the ability of HSV-1 to enter cells and spread from cell-to-cell. The gD/receptor interaction is essential to initiate viral entry and cell-to-cell virus transfer as these steps occr through the cooperative and fusogenic action of HSV-1 glycoproteins gD, gB, gH/gL and host cell receptors. The second molecular therapy will originate from a small molecule, which we have identified as a novel autophagy booster. Since HSV-1 tends to suppress autophagy, the molecules that moderately augment autophagy can show unprecedented promise as highly effective inhibitors against viral infections and their potential use as a topical agent to combat ocular infections can yield a very effective therapy. Our preliminary results show that the candidate molecule, Iazovir, enhances autophagy, which in turn, results in a significant loss of viral infection including an almost complete loss of viral proteins and DNA. Thus, the second goal of this proposal is to test the hypothesis that an autophagy enhancer will limit virus growth and demonstrate high therapeutic efficacy in the cornea. Ultimately, we will test the exciting possibility that a combination therapy containing the Aptamer and Iazovir will generate strong synergistic effects including higher efficacy and faster recovery time and define a new series of antiviral drugs against HSV-1 infection. To conclude, we propose to test a series of new and promising molecular treatments and define new and more effective ways to prevent and control ocular herpes symptoms and diseases.
HSV-1 infection is one of the most serious eye infections in the U.S. and a major cause of virus-induced blindness. Currently, there is no cure against lifelong HSV-1 infection and many patients suffering from herpes stromal keratitis (HSK) suffer vision loss. Here, we will perform drug development studies using two molecules, a novel RNA aptamer that binds HSV-1 envelope glycoprotein gD and an autophagy booster molecule, Iazovir. Analysis of these high efficiency inhibitors will guide new molecular therapies to significantly reduce the problems associated with HSV-1 ocular infection.
|Koujah, Lulia; Suryawanshi, Rahul K; Shukla, Deepak (2018) Pathological processes activated by herpes simplex virus-1 (HSV-1) infection in the cornea. Cell Mol Life Sci :|
|Agelidis, Alex M; Hadigal, Satvik R; Jaishankar, Dinesh et al. (2017) Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1. Cell Rep 20:439-450|
|Duggal, Neil; Jaishankar, Dinesh; Yadavalli, Tejabhiram et al. (2017) Zinc oxide tetrapods inhibit herpes simplex virus infection of cultured corneas. Mol Vis 23:26-38|
|Thakkar, Neel; Jaishankar, Dinesh; Agelidis, Alex et al. (2017) Cultured corneas show dendritic spread and restrict herpes simplex virus infection that is not observed with cultured corneal cells. Sci Rep 7:42559|
|Thakkar, Neel; Yadavalli, Tejabhiram; Jaishankar, Dinesh et al. (2017) Emerging Roles of Heparanase in Viral Pathogenesis. Pathogens 6:|
|Yadavalli, Tejabhiram; Agelidis, Alex; Jaishankar, Dinesh et al. (2017) Targeting Herpes Simplex Virus-1 gD by a DNA Aptamer Can Be an Effective New Strategy to Curb Viral Infection. Mol Ther Nucleic Acids 9:365-378|
|Jaishankar, Dinesh; Buhrman, Jason S; Valyi-Nagy, Tibor et al. (2016) Extended Release of an Anti-Heparan Sulfate Peptide From a Contact Lens Suppresses Corneal Herpes Simplex Virus-1 Infection. Invest Ophthalmol Vis Sci 57:169-80|
|Agelidis, Alex M; Shukla, Deepak (2015) Cell entry mechanisms of HSV: what we have learned in recent years. Future Virol 10:1145-1154|