Development of a Small Molecule Inhibitor for EBV Latent Infection

EBV潜伏感染小分子抑制剂的研制

• 批准号: 8252888
• 负责人: Mark E McDonnell
• 金额: $ 24.56万
• 依托单位: VIRONIKA, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252888
• 关键词: Advanced Development; Animal Model; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biological; Biological Assay; Biological Availability; Burkitt Lymphoma; Carcinogens; Cell Line; Cell Survival; Cells; Central Nervous System Lymphoma; Characteristics; Chemicals; Clinical; Collaborations; Complement; Data; Development; Development Plans; Disease; Drug Formulations; Drug effect disorder; EBV-associated disease; EBV-associated malignancy; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Fluorescence Polarization; Foxes; Funding; Generations; Genetic; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immunosuppression; Incidence; Individual; Inhibitory Concentration 50; Lead; Link; Luciferases; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Metabolism; Methods; Modeling; Mus; Nasopharynx Carcinoma; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Property; Protein Binding Domain; Proteins; Quantitative Structure-Activity Relationship; Research; Resources; Safety; Series; Small Business Innovation Research Grant; Solubility; Source; Stomach Carcinoma; T-Cell Lymphoma; The Wistar Institute; Therapeutic; Therapeutic Agents; Toxicology; Transplant Recipients; Viral; Viral Genome; World Health Organization; analog; base; cell growth; cell transformation; chemical stability; clinical practice; cytotoxicity; experience; gammaherpesvirus; high throughput screening; immunosuppressed; in vivo; indexing; inhibitor/antagonist; killings; latent infection; lead series; lytic replication; meetings; model development; mouse model; novel; novel therapeutics; physical property; pre-clinical; prevent; programs; small molecule; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this SBIR research program is to develop a novel small molecule inhibitor of latent 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 latency that wil provide an important therapeutic strategy to treat EBV-associated diseases. 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 EBV-specific 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 screened over 600,000 compounds in our primary HTS screen. Using hit-to-lead filtering approaches, we identified one lead series and two alternative backup series that have high potency in biochemical inhibitor assays and high selectivity in multiple cell-based assays, including selective killing of EBV+ lymphoma cell lines. Our lead compound has efficacy in an animal model of EBV lymphomagenesis. In this Phase 1 proposal, we will partner with Fox Chase Chemical Diversity Center 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 latent EBV infection and its associated malignancies. PUBLIC HEALTH RELEVANCE: The research program described in 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 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 latent infection.

描述（由申请人提供）：该SBIR研究计划的目的是开发一种新型的潜在爱泼斯坦 - 巴尔病毒（EBV）感染的小分子抑制剂。 EBV是一种普遍存在的γ-疱疹病毒，已被世界卫生组织归类为人类致癌。 Vironika及其财团合作伙伴Wistar Institute和Fox Chase Chase Drivess Center，Inc。将开发出一种高度特异性且有效的EBV潜伏期抑制剂，Will为治疗EBV相关疾病提供了重要的治疗策略。潜在感染与多种人类恶性肿瘤有关，包括伯基特的淋巴瘤，鼻咽癌，霍奇金的淋巴瘤，胃癌和免疫细胞B-细胞淋巴瘤在免疫抑制期间。目前，尚无针对潜在感染的EBV特异性疗法，因此仍然不可能有效治疗或预防与EBV相关的疾病。潜在感染取决于病毒编码的蛋白质，该蛋白在病毒基因组的复制和维持中起作用。该蛋白质的遗传和生物学破坏会阻止病毒潜在感染和EBV依赖性B细胞生长。该蛋白的结合结构域在结构和生化上已经表征，并作为靶向小分子抑制EBV感染的理想分子。我们在主HTS屏幕中筛选了600,000多种化合物。使用命中率滤波方法，我们确定了一个铅系列和两个替代备用系列，这些系列具有较高的生化抑制剂测定效力，并且在多个基于多个细胞的测定中具有高选择性，包​​括选择性杀死EBV+淋巴瘤细胞系。我们的铅化合物在EBV淋巴细胞化动物模型中具有功效。在此第1阶段的建议中，我们将与Fox Chase化学多样性中心合作，使用药物化学方法和广泛的生化和生物学分析来促进铅化合物，以验证药物作用机制。在第2阶段，我们将把高级潜在客户发展为临床前候选者。该SBIR计划的最终目标是开发一种新型的小分子治疗剂，以治疗潜在的EBV感染及其相关的恶性肿瘤。 公共卫生相关性：本提案中描述的研究计划将减少爱泼斯坦 - 巴尔病毒（EBV）的潜在（非活动）感染的发生率。潜在EBV已被归类为人类致癌物，与伯基特的淋巴瘤，霍奇金的淋巴瘤和鼻咽癌有关。该提案中开发的产物是第一种专门破坏EBV潜在感染的治疗小分子药物。