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: 8433306
• 负责人: Mark E McDonnell
• 金额: $ 9.11万
• 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 2014-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433306
• 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; public health relevance; 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.

描述（由申请人提供）：本SBIR研究项目的目标是开发一种新型的小分子潜伏eb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与其合作伙伴Wistar研究所和Fox Chase化学多样性中心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有关，包括免疫抑制期间的伯基特淋巴瘤、鼻咽癌、霍奇金淋巴瘤、胃癌和免疫母细胞b细胞淋巴瘤。目前，还没有针对潜伏感染的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。潜伏感染依赖于病毒编码蛋白，该蛋白在病毒基因组的复制和维持中起作用。该蛋白的遗传和生物学破坏可阻断病毒潜伏感染和eb病毒依赖的b细胞生长。该蛋白的结合结构域已在结构上和生物化学上进行了表征，可作为靶向小分子抑制EBV感染的理想分子。我们已经在初级HTS筛选中筛选了超过60万种化合物。使用命中-导联过滤方法，我们确定了一个先导系列和两个备选备选系列，它们在生化抑制剂检测中具有高效，在多种基于细胞的检测中具有高选择性，包括选择性杀死EBV+淋巴瘤细胞系。我们的先导化合物对EBV淋巴瘤形成的动物模型有效。在这个i期项目中，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学分析来验证药物作用机制，推进先导化合物的研发。在第二阶段，我们将把先进的先导药物开发成临床前先导候选药物。这个SBIR项目的最终目标是开发一种新的小分子治疗剂来治疗潜伏的EBV感染及其相关的恶性肿瘤。