Development of a Small Molecule Inhibitor for EBV Lytic Reactivation

EBV 裂解再激活小分子抑制剂的开发

• 批准号: 9201592
• 负责人: Ursula D Ramirez
• 金额: $ 30万
• 依托单位: VIRONIKA, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-19 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201592
• 关键词: Address; Animal Model; B-Cell Lymphomas; BZLF1 gene; Biochemical; Biological; Biological Assay; Biotechnology; Burkitt Lymphoma; Calorimetry; Carcinogens; Cells; Chemicals; Chronic; Collaborations; DNA Binding; DNA biosynthesis; Detection; Development; Disease; Drug Kinetics; Drug effect disorder; EBV-associated disease; EBV-associated malignancy; Epithelial Cells; Epstein-Barr Virus Infections; Etiology; Fluorescence Polarization; Foxes; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immediate-Early Genes; Immune; Immune System Diseases; Immunocompromised Host; Immunosuppression; Incidence; Lead; Libraries; Lymphoid Cell; Lymphomagenesis; Lytic; Lytic Phase; Lytic Virus; Malignant Neoplasms; Measures; Mediating; Medical; Methods; Modeling; Monitor; Multiple Sclerosis; Nasopharynx Carcinoma; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Oncogenic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Population; Protein Binding Domain; Proteins; Quantitative Structure-Activity Relationship; Research; Research Project Grants; Risk; Risk Factors; Roentgen Rays; Seeds; Small Business Innovation Research Grant; Stomach Carcinoma; Structure; Surface Plasmon Resonance; T-Cell Lymphoma; Testing; The Wistar Institute; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transactivation; Transcription Coactivator; Transcriptional Activation; Validation; Viral; Viral Genes; Virus; Virus Diseases; World Health Organization; Xenograft Model; Xenograft procedure; abstracting; analog; base; cell growth; counterscreen; drug discovery; experience; gammaherpesvirus; gene product; high throughput screening; improved; in vivo; inhibitor/antagonist; lead series; lytic replication; neoplastic cell; novel; pre-clinical; prevent; programs; public health relevance; skills; small molecule; small molecule inhibitor; small molecule therapeutics; targeted treatment; treatment strategy; tumorigenesis; viral DNA

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 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.

摘要： 该SBIR研究计划的目标是开发一种新型的小分子裂解Epstein-Barr抑制剂 病毒(EBV)感染EBV是一种普遍存在的伽玛疱疹病毒，已被世界卫生组织列为 是一种人类致癌物质。Vironika与其财团合作伙伴Wistar Institute和Fox Chase 化学多样性中心公司将开发一种高度特异和有效的EBV裂解(再)激活抑制剂， 将为治疗EBV相关疾病提供重要的治疗策略。EBV感染与 患有多种人类恶性肿瘤，包括伯基特淋巴瘤、鼻咽癌、霍奇金淋巴瘤 淋巴瘤、胃癌和免疫母细胞B细胞淋巴瘤在免疫抑制期间。目前， 不存在针对溶解(重新)激活的EBV特异性疗法，因此仍然不可能有效地 治疗或预防EBV相关疾病。裂解性感染依赖于病毒编码的蛋白质ZTA，它 在(重新)激活裂解病毒周期中起作用。该蛋白的结合区已被鉴定 在结构和生化上，是靶向抑制EB病毒小分子的理想分子 感染。我们已经在HTS的主屏幕上筛选了超过42万种化合物。初步的命中是 通过反筛过滤，樱桃采摘并以三重单浓度分析形式验证。 在通过这些标准的42次命中中，确定了三种化学类型。在此第一阶段计划中，我们 将进一步验证这些命中并生成有针对性的文库，以利用药物推进先导化合物 化学方法和广泛的生化和生物学分析，以验证药物的作用机制。在……里面 第二阶段，我们将把我们的先进线索发展为临床前候选线索。这项SBIR的最终目标是 计划是开发一种新的小分子治疗剂来治疗裂解性EBV感染及其相关的 恶性肿瘤。