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 研究计划的目标是开发一种新型小分子潜伏性 Epstein-Barr 病毒 (EBV) 感染抑制剂。 EBV 是一种普遍存在的γ-疱疹病毒，已被世界卫生组织列为人类致癌物。 Vironika 与其财团合作伙伴 Wistar Institute 和 Fox Chase Chemical Diversity Center, Inc. 将开发一种高度特异性和有效的 EBV 潜伏期抑制剂，这将为治疗 EBV 相关疾病提供重要的治疗策略。潜伏感染与多种人类恶性肿瘤相关，包括伯基特淋巴瘤、鼻咽癌、霍奇金淋巴瘤、胃癌和免疫抑制期间的免疫母细胞B细胞淋巴瘤。目前，尚无针对潜伏感染的 EBV 特异性疗法，因此仍然不可能有效治疗或预防 EBV 相关疾病。潜伏感染取决于病毒编码的蛋白质，该蛋白质在病毒基因组的复制和维持中发挥作用。这种蛋白质的遗传和生物学破坏可阻止病毒潜伏感染和 EBV 依赖性 B 细胞生长。该蛋白的结合域已在结构和生化方面得到表征，可作为靶向小分子抑制 EBV 感染的理想分子。我们在初级 HTS 筛选中筛选了超过 600,000 种化合物。使用命中先导过滤方法，我们确定了一个先导系列和两个替代备用系列，它们在生化抑制剂测定中具有高效能，在多种基于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。我们的先导化合物对 EBV 淋巴瘤发生的动物模型有效。在这一第一阶段提案中，我们将与 Fox Chase 化学多样性中心合作，利用药物化学方法和广泛的生化和生物分析来开发先导化合物，以验证药物作用机制。在第二阶段，我们将把我们的先进先导药物开发成临床前先导候选药物。该 SBIR 项目的最终目标是开发一种新型小分子治疗剂来治疗潜伏 EBV 感染及其相关恶性肿瘤。 公共健康相关性：本提案中描述的研究计划将减少 Epstein-Barr 病毒 (EBV) 潜伏（非活动）感染的发生率。潜伏 EBV 已被列为人类致癌物，与伯基特淋巴瘤、霍奇金淋巴瘤和鼻咽癌有关。该提案中正在开发的产品是第一个专门破坏EBV潜伏感染的治疗性小分子药物。