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 Burkitt's lymphoma, nasopharyngeal carcinomas, Hodgkin's lymphoma, gastric carcinomas, and immunoblastic B-cell lymphoma'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 420,000 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 42 hits that passed these criteria, three chemotypes were identified. In this Phase 1 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 2, 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 Statement: 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 Burkitt's lymphoma, Hodgkin'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.
Project Terms: abstracting; Address; analog; Animal Model; B-Cell Lymphomas; base; Biochemical; Biological; Biological Assay; Biotechnology; Burkitt Lymphoma; BZLF1 gene; Calorimetry; Carcinogens; cell growth; Cells; Chemicals; Chronic; Collaborations; counterscreen; Detection; Development; Disease; DNA Binding; DNA biosynthesis; drug discovery; Drug effect disorder; Drug Kinetics; EBV-associated disease; EBV-associated malignancy; Epithelial Cells; Epstein-Barr Virus Infections; Etiology; experience; Fluorescence Polarization; Foxes; gammaherpesvirus; Gene Expression; gene product; Generations; Genes; Genetic Transcription; Goals; Herpesviridae; high throughput screening; Hodgkin Disease; Human; Human Herpesvirus 4; Immediate-Early Genes; Immune; Immune System Diseases; Immunocompromised Host; improved; in vivo; Incidence; inhibitor/antagonist; Lead; lead series; Libraries; Lymphoid Cell; Lymphomagenesis; Lytic; Lytic Phase; lytic replication; Lytic Virus; Malignant Neoplasms; Measures; Mediating; Medical; Methods; Modeling; Monitor; Multiple Sclerosis; Nasopharynx Carcinoma; Natural immunosuppression; Neoplasm Metastasis; neoplastic cell; Non-Hodgkin's Lymphoma; novel; Oncogenic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Population; pre-clinical; prevent; programs; Protein Binding Domain; Proteins; public health relevance; Quantitative Structure-Activity Relationship; Research; Research Project Grants; Risk; Risk Factors; Roentgen Rays; Seeds; skills; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; small molecule therapeutics; Stomach Carcinoma; Structure; Surface Plasmon Resonance; T-Cell Lymphoma; targeted treatment; Testing; The Wistar Institute; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transactivation; Transcription Coactivator; Transcriptional Activation; treatment strategy; tumorigenesis; Validation; Viral; viral DNA; Viral Genes; Virus; Virus Diseases; World Health Organization; Xenograft Model; Xenograft procedure
