FOX CHASE CHEMICAL DIVERSITY CENTER INC. — Department of Health and Human Services STTR Phase I: N

Description

ABSTRACT Infection of the eye by Herpes Simplex Virus HSV can result in Herpes Keratitis HK which is the leading cause of corneal blindness worldwide In the U S nearly individuals experience ocular herpes infections that are often recurrent and culminate in progressive corneal scarring and loss of vision The gold standard of care for HK is treatment with Acyclovir ACV that targets HSV thymidine kinase TK Although ACV is extremely effective in both oral and genital herpes with negligible drug failure the emergence of viral resistant mutants in of ocular HK patients is compelling Significantly the mechanism of drug resistance is directly related to mutational alterations in the TK gene of HSV isolated from HK patients unresponsive to ACV This high level of resistance can be prevented if ACV is combined with a second antiviral directed against a different target to block mutants that escape either drug One new class of antiviral targets is the processivity factors PFs that are essential to keep their cognate viral polymerases Pols tethered to the template for continuous viral DNA synthesis Our objective is to develop early lead antiviral compounds that are directed against the HSV processivity factor PF We have now identified a potent early Lead Z which blocks infection of HSV with an EC of nM We have also identified structurally diverse backup leads With the future requirement of animal model validation we are in a unique position to treat multiple feline patients Phase from the UPenn Vet School who are infected with the homologous Feline Herpes Virus FHV These feline patients provide a close and natural model of human herpes keratitis that can be followed for extended periods for recurrent infections We have now cloned the FHV PF Pol genes which share considerable homologies to those of HSV and have validated that the majority of our compounds that block HSV also block FHV infection with similar potencies Even though the feline model is highly attractive our experimental design is focused such that analogs that are singly superior for HSV but not FHV will be developed further Phase using traditional models The Aims of this proposal are tightly linked employing medicinal chemistry as an iterative process to improve the therapeutic index of Z by generating new analogs that have increased potency with no detectable toxicities Rational design based on docking of Z to the known crystal structure of the PF target protein will be one means on producing new Leads Backup Leads will also be optimized should properties such as solubility or stability need to be enhanced Phase Analogs will be tested for blocking processive DNA synthesis in vitro physical binding to the PF target protein toxicity and cell proliferation antiviral activities in primary feline corneal epithelial cells and in the human D corneal tissue The human D corneal tissue will be tested further for permeability and histology NARRATIVE Infection of the eye by Herpes Simplex Virus can result in ocular Herpes Keratitis which is the leading cause of corneal blindness in the USA and the world The gold standard for treatment is the herpes antiviral acyclovir ACV However the significant emergence of ACV resistant HSV mutants in ocular Herpes Keratitis necessitates the development of a new safe and effective ocular antiviral drug that can be used alone or in combination with ACV to prophylactically prevent as well as treat acute herpes eye infections The goal of this project is to obtain a new and safe antiviral compound that is directed against a proven novel target the herpes virus Processivity Factor The Processivity Factor antiviral will block viral DNA replication by a mechanism that is distinct from the ACV antiviral As such the two antivirals together should be nearly effective in preventing emergence of drug resistant mutants and eliminate the devastating loss of sight that results from ocular Herpes Keratitis