Chronic, long-term infection with herpes simplex virus (HSV) remains a significant unmet medical need. It is estimated that ~800,000 individuals in the US will be newly infected with HSV1 or HSV2 each year, and that the total infection rate approaches 80% for adults over 50 yrs of age. Long-term latent infection and chronic reactivation of HSV1 and HSV2 remain a significant source of morbidity, including a major source of blindness and encephalitis. Presently, there are no vaccines or small molecule drugs that selectively treat and eliminate the latent infection. Here, we propose to develop new chemical entity small molecule drugs to target and treat latent forms of HSV infection in human neurons. HSV express only one viral transcript, termed LAT, during neuronal latency. LAT is known to be a stable intron that is highly conserved among all viral strains across both HSV1 and HSV2 species. LAT is important for maintaining viral latency and confers resistance to apoptosis for latently infected neurons. The most highly conserved substructure of LAT is the stable 3 stem loop containing a non- canonical branch point sequence that prevents debranching by the cellular enzyme DBR1. Genetic studies reveal that disruption of the stem-loop and branch point structure destabilizes LAT and eliminates its functional activity. Here, we propose to carry out high-throughput screenings with the recently developed FRET-based biochemical assay and will develop and implement cell-based assays to identify selective interacting, RNA-structure disrupting molecules that have favorable drug-like properties using industry standard principles of medicinal chemistry and fragment-based drug design. The product that ultimately results from this proposal is a small molecule inhibitor that selectively binds and disrupts the function of LAT RNA in HSV neuronal latency, and can be further developed for the treatment of HSV latency and associated diseases.
Public Health Relevance Statement: Project Narrative The goal of the SBIR proposal is to develop novel small molecule drug candidate for the treatment of Herpes Simplex Virus (HSV) latent infection in neurpons. HSV latency is associated with ocular keratitis, blindness, and encephailitis, as well as chronic reactivation leading to significant discomfort and morbidity. HSV latent infection may also be linked to Alzheimers disease. We propose to target a viral non-coding RNA, LAT, expressed at high-levels in all HSV latent infection in neurons, contributing to viral gene control, neuronal cell survival, and immune evasion, and therefore, an attractive target for small molecule therapeutic intervention.
Project Terms: Adult; Age; Alzheimer's Disease; Animal Model; Apoptosis; base; Binding; Biochemical; Biological Assay; Biotechnology; Blindness; Cell model; Cell Survival; Cells; Chemicals; Chronic; Clinical Trials; Collaborations; counterscreen; Development; Disease; drug candidate; Drug Design; Drug Kinetics; Encephalitis; Enzymes; Epstein-Barr virus encoded RNA 1; Epstein-Barr Virus latency; first-in-human; Fluorescence Resonance Energy Transfer; Foxes; Ganglia; Genetic study; Goals; Herpesvirus 1; high throughput screening; HIV; Human; human disease; Human Herpesvirus 2; Human Herpesvirus 4; imaging probe; Immune Evasion; Immune System Diseases; Individual; Industry Standard; Infection; inhibitor/antagonist; Introns; Keratitis; latent infection; Latent Virus; Latent virus infection phase; Lead; Legal patent; Libraries; Link; Luciferases; Medical; meetings; Methods; Modeling; Monitor; Morbidity - disease rate; Neurons; novel; Nuclear Antigens; off-patent; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; pharmacophore; Phase; prevent; programs; Property; Quantitative Structure-Activity Relationship; Resistance; RNA; RNA Splicing; screening; Seeds; Simplexvirus; Site; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; small molecule therapeutics; Source; Specificity; stem; Structure; Surface Plasmon Resonance; The Wistar Institute; Therapeutic Intervention; Transcript; Trust; United States Food and Drug Administration; Untranslated RNA; Vaccines; Viral; Viral Genes; Virus Diseases; Virus Latency
