Development of a Small Molecule Inhibitor for EBV Lytic Reactivation

摘要： 该SBIR研究计划的目标是开发一种新型的小分子溶解性EB病毒抑制剂 病毒（EBV）感染。EBV是一种普遍存在的γ-疱疹病毒，已被世界卫生组织分类为 组织作为人类致癌物。Vironika及其联盟伙伴Wistar Institute和Fox Chase 化学多样性中心，公司，将开发一种高度特异性和有效的EBV裂解（再）激活抑制剂， 将为治疗EBV相关疾病提供重要的治疗策略。EBV感染与 多种人类恶性肿瘤，包括伯基特淋巴瘤，鼻咽癌，霍奇金淋巴瘤， 淋巴瘤、胃癌和免疫母细胞性B细胞淋巴瘤。目前， 不存在靶向裂解（再）激活的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。裂解性感染依赖于病毒编码的蛋白质ZTA， 在裂解病毒循环的（再）活化中起作用。该蛋白的结合结构域已被表征 结构和生物化学上，并作为靶向小分子抑制EBV的理想分子 感染我们在初级HTS筛选中筛选了超过420，000种化合物。初步调查显示 通过反筛过滤，挑选并以一式三份的单一浓度测定形式验证。 在通过这些标准的42个命中中，鉴定了三种化学型。在第一阶段，我们 将进一步验证这些命中，并产生集中的库，以推进使用药物的先导化合物 化学方法和广泛的生物化学和生物学分析，以验证药物作用机制。在 第二阶段，我们将把我们的高级电极导线开发成临床前电极导线候选者。本SBIR的最终目标 该项目旨在开发一种新的小分子治疗剂来治疗溶解性EBV感染及其相关疾病。 恶性肿瘤。

Abstract: The goal of this SBIR research program is to develop a novel small molecule inhibitor of lytic 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 lytic (re)activation that will provide an important therapeutic strategy to treat EBV-associated diseases. EBV 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 lytic (re)activation, and therefore it remains impossible to effectively treat or prevent EBV-associated disease. The lytic infection depends on a viral encoded protein, ZTA, which functions in the (re)activation of the lytic virus cycle. 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 420,000 compounds in our primary HTS screen. Preliminary hits were filtered by counterscreen, and cherry picked and validated in triplicate single concentration assay formats. Among the 42 hits that passed these criteria, three chemotypes were identified. In this Phase 1 proposal, we will further validate these hits and generate focused libraries 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 lytic EBV infection and its associated malignancies.