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的潜伏性EB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.将开发高度特异性和有效的EBV潜伏期抑制剂，其将提供治疗EBV相关疾病的重要治疗策略。潜伏性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性B细胞淋巴瘤。目前，不存在靶向潜伏感染的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的蛋白质，该蛋白质在病毒基因组的复制和维持中起作用。这种蛋白质的遗传和生物破坏阻断病毒潜伏感染和EBV依赖性B细胞生长。该蛋白的结合结构域已在结构和生物化学上表征，并且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。使用命中到铅过滤方法，我们确定了一个铅系列和两个替代备份系列，具有高效力的生化抑制剂测定和高选择性，在多个基于细胞的测定，包括EBV+淋巴瘤细胞系的选择性杀伤。我们的先导化合物在EBV淋巴瘤发生的动物模型中有效。在第一阶段的提案中，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分析来推进先导化合物，以验证药物作用机制。在第二阶段，我们将把先进的电极导线开发成临床前电极导线候选产品。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性EBV感染及其相关恶性肿瘤。 公共卫生相关性：本提案中描述的研究计划将降低EB病毒（EBV）潜伏（非活动性）感染的发生率。潜伏性EBV已被归类为人类致癌物，并与伯基特淋巴瘤、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种专门破坏EBV潜伏感染的治疗性小分子药物。