Combating Corneal HSV Infection with Novel Dynasore Analogues

PROJECT SUMMARY Herpes simplex viruses 1 and 2 (HSV-1, -2) are epidemic worldwide. Globally, it has been estimated that approximately 1.5 million cases of HSV-related ocular infection occur every year, with 40,000 of those ending up with longstanding visual damage. The virus’s ability to spread through airborne droplets contributes to its high degree of transmissibility, often leading to blinding corneal ulcers. Current standards of care include concurrent treatment with anti-virals and corticosteroids, which are effective, but have side effects that can compromise visual acuity. Similarly, during severe inflammatory conditions, corneal transplantation is required to preserve vision. Therefore, there is a need to develop therapies that can prevent or reduce the ability of HSV-1 to infect ocular surface epithelial cells, which would then mitigate subsequent inflammation and loss of visual acuity. It has been suggested that molecules contributing to more than one step in the HSV life cycle may serve more effectively as targets for new preventative or therapeutic drugs. Dynasore is a cell-permeant small molecule developed to target the GTPase activities of classic dynamins, a family of molecules that participate in several endocytic pathways and in several steps in the HSV life cycle. Indeed, dynasore has been demonstrated to have pleiotropic effects against HSV infection, including inhibition of cell uptake, intracellular trafficking, capsid assembly, and cell-to-cell spread. The applicant company recently undertook a project to develop dynasore analogues to protect against epitheliopathy in dry eye (DE) disease. The team identified 3 lead compounds that inhibit clathrin-mediated endocytosis with greater potency than dynasore. Two of the leads are novel chemical entities (NCEs) substantially different from dynasore, thus are likely to be patentable. Importantly, the team now demonstrates their antiviral effect specifically against HSV infection of corneal mucosal epithelial cells in culture, although with different rank potencies than for cytoprotection. The goal of this proposal is to refine the structure-activity relationship for antiviral effect against HSV. From this screen, up to 5 lead compounds with optimized anti-HSV1 profiles will be selected. Then, using a mouse model of HSK, the most efficacious compound(s) will be identified to take forward for further development. Following completion of this Phase I effort, the team will have defined the SAR for inhibition of HSV-1 infection and HSK in a mouse model. During Phase II, the team will prepare additional compounds to evaluate absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements. Finally, the team will fine tune the formulation and dosage to maximize efficacy, shelf life and ease of application, while decreasing any toxic or off-target effects.