Development of a Small Molecule Inhibitor for EBV Latent Infection

描述(申请人提供)：该SBIR研究计划的目标是开发一种新型的小分子抑制潜伏性EB病毒(EBV)感染的药物。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人类致癌物。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潜伏期抑制剂，这将为治疗EBV相关疾病提供一种重要的治疗策略。潜伏感染与多种人类恶性肿瘤有关，包括Burkitt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特异性治疗方法，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护中发挥作用。这种蛋白的遗传和生物破坏阻止了病毒潜伏感染和依赖EBV的B细胞生长。该蛋白的结合域已被结构和生化鉴定，是靶向抑制EBV感染的理想小分子分子。我们已经在HTS的主屏幕上筛选了60多万种化合物。使用Hit-to-Lead筛选方法，我们确定了一个先导系列和两个备用系列，它们在生化抑制剂检测中具有高效力，在多种细胞检测中具有高选择性，包括选择性杀伤EBV淋巴瘤细胞系。我们的先导化合物在EBV淋巴肿大的动物模型中具有疗效。在这一阶段的提案中，我们将与福克斯大通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推进先导化合物的开发，以验证药物作用的机制。在第二阶段，我们将把我们的先进线索发展为临床前候选线索。这项SBIR计划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。

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.