# A new molecular therapy against ocular herpes

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $476,059

## Abstract

Herpes simplex virus type-1 (HSV-1) with limited treatment options is a leading cause of infectious blindness
and an important indication for corneal transplants in the US. The current treatment options include acyclovir
and its derivatives, ganciclovir and foscarnet. All these drugs primarily act upon viral thymidine kinase to inhibit
viral DNA replication and in essence have a similar mechanism of action. While these options are effective and
show promise in reducing ocular HSV-1 infection including herpes stromal keratitis (HSK), emergence of drug
resistance in the recent years has caused significant distress in the clinical care of ocular HSV-1 patients. As a
result, there exists an unmet need for the development of new treatments against HSV-1 especially the ones
that rely on novel modes of action. In our previous 3-year funding period we have characterized two candidates
that target two different stages of HSV-1 infection; viral entry and viral protein synthesis. Against viral entry a
highly effective anti-HSV-1 aptamer (DApt) was developed that targets HSV-1 glycoprotein D (gD). Similarly,
we demonstrated for the first time that a small molecule PDK-1 inhibitor, BX795, blocks HSV-1 protein
synthesis. Both candidates were tested in vivo for topical treatment of corneal HSV-1 infection and we reported
significant improvements in disease prognosis. The major goals for the next funding period are to: (1) improve
the in vivo efficacy of DApt, (2) understand the molecular basis of antiviral action by BX795, and (3) develop
BX795 for systemic treatment of ocular herpes. In the first specific aim, we propose several ways to improve
efficacy. We will engineer therapeutic contact lenses for sustained delivery of DApt, improve DApt formulation
to include permeating agents such as cylodextrins to increase the depth to which the aptamer is delivered into
the corneal tissue, and develop higher efficacy (synergistic or additive) drug combinations using DApt and
BX795 or a nucleoside analog. In the second specific aim, we will decode the molecular mechanisms
responsible for the antiviral activity of BX795 using both biased and unbiased approaches. Focus on the cap-
dependent translation pathways responsible for viral protein synthesis will constitute the biased approach; cell-
free and whole cell proteomic analyses using quantitative mass spectrometry and study of post translational
modifications will constitute unbiased approaches. In the third specific aim, we will comprehensively study the
pharmacokinetic and toxicological profiles of intravenously administered BX795. Using this data, we will finally
understand the safe and effective dosage of BX795 required for the effective inhibition of primary and
reactivated HSV-1 infection of the cornea using murine models of corneal infection. Taken together our studies
will establish novel antiviral mechanisms and help design new prophylactic and therapeutic ways to control
HSV-1 infection of the eye.

## Key facts

- **NIH application ID:** 10557908
- **Project number:** 5R01EY024710-08
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** DEEPAK SHUKLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $476,059
- **Award type:** 5
- **Project period:** 2015-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10557908

## Citation

> US National Institutes of Health, RePORTER application 10557908, A new molecular therapy against ocular herpes (5R01EY024710-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10557908. Licensed CC0.

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