Development of a Small Molecule Inhibitor for EBV Lytic Reactivation

Abstract The goal of this SBIR research program is to develop a novel small molecule inhibitor of lytic Epstein Barr Virus EBV infection EBV is a ubiquitous gamma herpesvirus that has been classified by the World Health Organization as a human carcinogen Vironika with its consortium partners the Wistar Institute and Fox Chase Chemical Diversity Center Inc will develop a highly specific and potent inhibitor of EBV lytic re activation that will provide an important therapeutic strategy to treat EBV associated diseases EBV infection is associated with multiple human malignancies including Burkittandapos s lymphoma nasopharyngeal carcinomas Hodgkinandapos s lymphoma gastric carcinomas and immunoblastic B cell lymphomaandapos s during immunosuppression Currently no EBV specific therapies exist that target lytic re activation and therefore it remains impossible to effectively treat or prevent EBV associated disease The lytic infection depends on a viral encoded protein ZTA which functions in the re activation of the lytic virus cycle 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 screened over compounds in our primary HTS screen Preliminary hits were filtered by counterscreen and cherry picked and validated in triplicate single concentration assay formats Among the hits that passed these criteria three chemotypes were identified In this Phase proposal we will further validate these hits and generate focused libraries to advance a lead compound using medicinal chemistry methods and extensive biochemical and biological analysis to validate mechanism of drug action In Phase we will develop our advanced leads into a pre clinical lead candidate The ultimate goal of this SBIR program is to develop a novel small molecule therapeutic agent to treat lytic EBV infection and its associated malignancies Public Health Relevance The research program described in this proposal will reduce the incidence of lytic re activation by Epstein Barr Virus EBV EBV has been classified as a human carcinogen and is associated with Burkittandapos s lymphoma Hodgkinandapos s lymphoma and nasopharyngeal carcinomas The product being developed in this proposal is the first therapeutic small molecule drug that specifically disrupts EBV lytic re activation