Screening of Epstein Barr Virus Replication (RMI)

Epstein Barr 病毒复制 (RMI) 筛选

• 批准号: 6879777
• 负责人: ELLIOTT D KIEFF
• 金额: $ 8.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879777
• 关键词: B lymphocyte; Epstein Barr virus; drug discovery /isolation; drug screening /evaluation; gene expression; high throughput technology; host organism interaction; immunopharmacology; latent virus infection; plasmids; small molecule; virus antigen; virus genetics; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Long term objective is to identify small molecules which can eradicate latent EBV genomes and latently infected cells. The specific objective is to identify chemical candidates that functionally inhibit EBNA1 in cells and in vitro. These molecules could be used to validate the importance of targeting EBNA1 for the elimination of EBV episomes and for halting the growth of latency III infected lymphocytes, in culture or in experimental models. This would provide a compelling model and perhaps a lead compound for approaches to the therapy or prevention of EBV associated PTLD, AIDS associated lymphoma. Although prevalent in all human populations, EBV is an important cause of lymphoma and in immune compromised people Disease (PTLD), various B and T cell Lymphoma (L) and Hodgkin's Lymphoma (HL). EBV replicates in oropharyngeal epithelial cells and establish latency in B lymphocytes. In B cells EBV can establish 3 types of latency. Latency Ill, EBV expresses 6 EB Nuclear antigens (EBNAs) and two integral membrane proteins (LMP1 and 2) and causes lymphocyte proliferation, which is indistinguishable from PTLD. Normally, latency type lll cells are recognized by T lymphocytes and are readily eliminated as immune response develop. Some infected B cells persist in latency type II, wherein only EBNA1, LMP1 and LMP2 are expressed or, in latency type I, wherein only EBAN1 is expressed. EBNA1 is not processed by proteasome pathways and thereby escapes recognition by CD8 cytotoxic T cells. EBNA1 is the only protein required for EBV DNA persistence as extrachromosomal episomes. EBNA1 binds to cognate sequences in oriP and to chromosomes, enabling EBV DNA to be replicated, maintained, transcribed. Therefore, inhibition of EBNA1 function is likely to be efficient way to eradicate EBV infected cells from body.

描述（由申请人提供）：长期目标是鉴定能够根除潜伏EBV基因组和潜伏感染细胞的小分子。 具体目标是鉴定在细胞中和体外功能性抑制EBNA1的化学候选物。 这些分子可用于验证在培养物或实验模型中靶向EBNA1对于消除EBV游离体和停止潜伏期III感染的淋巴细胞的生长的重要性。 这将为治疗或预防EBV相关PTLD、AIDS相关淋巴瘤的方法提供一个令人信服的模型和可能的先导化合物。 尽管在所有人群中普遍存在，但EBV是淋巴瘤和免疫受损人群疾病（PTLD）、各种B和T细胞淋巴瘤（L）和霍奇金淋巴瘤（HL）的重要原因。 EBV在口咽上皮细胞中复制并在B淋巴细胞中建立潜伏期。 在B细胞中，EBV可以建立3种类型的潜伏期。 潜伏期III，EBV表达6种EB核抗原（EBNAs）和两种整合的膜蛋白（LMP 1和2），并引起淋巴细胞增殖，这与PTLD难以区分。 通常，潜伏III型细胞被T淋巴细胞识别，并且随着免疫应答的发展而容易被消除。 一些受感染的B细胞以潜伏期II型持续存在，其中仅EBNA 1、LMP 1和LMP 2表达，或者以潜伏期I型持续存在，其中仅EBAN 1表达。 EBNA1不被蛋白酶体途径加工，从而逃避CD8细胞毒性T细胞的识别。 EBNA1是EBV DNA作为染色体外附加体持续存在所需的唯一蛋白质。 EBNA1与oriP中的同源序列和染色体结合，使EBV DNA能够复制、维持、转录。 因此，抑制EBNA1功能可能是从体内清除EBV感染细胞的有效方法。