Novel Inhibitors of Latent Epstein Barr Virus Infection

描述（由申请人提供）：由Vironika及其联盟合作伙伴Wistar研究所提出的SBIR计划产生的产品是一种新的（第一种）小分子候选药物，用于EB病毒（EBV）潜伏感染及其相关病理。EBV是一种流行的人类疱疹病毒，已被世界卫生组织列为人类致癌物。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性B细胞淋巴瘤。目前，没有针对潜伏感染的治疗方法，因此仍然不可能有效治疗或预防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。我们已经开发了一种用于监测该靶标的结合活性的分子测定法，并且已经证明该测定法在高通量形式下表现良好。在这个1期提案中，我们将使用我们的检测方法筛选小分子化合物文库，并使用基于细胞的病毒基因组维持和细胞毒性检测方法验证潜在的抑制剂。如果成功，我们将在潜伏性EBV感染的啮齿动物模型中进一步表征第2阶段的线索。公共卫生相关性：该提案将降低爱泼斯坦巴尔病毒（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Bukitt淋巴瘤、霍奇金淋巴瘤和鼻咽癌相关。正在开发的产品是第一种专门破坏EBV潜伏感染的药物。

DESCRIPTION (provided by applicant): The product that will result from this SBIR program, proposed by Vironika and its consortium partner, The Wistar Institute, is a new (the first) small molecule drug candidate for Epstein-Barr virus (EBV) latent infection, and its associated pathologies. EBV is a prevalent human herpesvirus that has been classified by the World Health Organization as a human carcinogen. The 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 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 developed a molecular assay for monitoring the binding activity of this target, and have demonstrated that this assay performs well in high throughput format. In this Phase 1 proposal, we will use our assay to screen small molecule compound libraries and will validate potential inhibitors using cell-based assays of viral genome maintenance and cytotoxicity. If successful, we will further characterize leads in Phase 2 in rodent models of latent EBV infection. PUBLIC HEALTH RELEVANCE: 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 Bukitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinomas. The product being developed here is the first drug that specifically disrupts EBV latent infection.