Novel Inhibitors of Latent Epstein Barr Virus Infection

DESCRIPTION (provided by applicant): The product that will result from this SBIR program, proposed by Vironika and its consortium partner, The Wistar Institute, is a new (the first) small molecule drug candidate for Epstein-Barr virus (EBV) latent infection, and its associated pathologies. EBV is a prevalent human herpesvirus that has been classified by the World Health Organization as a human carcinogen. The latent infection is associated with multiple human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinomas, Hodgkin's lymphoma, gastric carcinomas, and immunoblastic B-cell lymphoma's during immunosuppression. Currently, no therapies exist that target latent infection, and therefore it remains impossible to effectively treat or prevent EBV-associated disease. The latent infection depends on a viral encoded protein which functions in the replication and maintenance of the viral genome. Genetic and biological disruption of this protein blocks viral latent infection and EBV-dependent B-cell growth. The binding domain of this protein has been characterized structurally and biochemically, and serves as an ideal molecule for targeted small molecule inhibition of EBV infection. We have developed a molecular assay for monitoring the binding activity of this target, and have demonstrated that this assay performs well in high throughput format. In this Phase 1 proposal, we will use our assay to screen small molecule compound libraries and will validate potential inhibitors using cell-based assays of viral genome maintenance and cytotoxicity. If successful, we will further characterize leads in Phase 2 in rodent models of latent EBV infection. PUBLIC HEALTH RELEVANCE: This proposal will reduce the incidence of latent (non-active) infection by Epstein Barr Virus (EBV). Latent EBV has been classified as a human carcinogen and is associated with Bukitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinomas. The product being developed here is the first drug that specifically disrupts EBV latent infection.