Inhibitors of Kaposi???s Sarcoma Herpesvirus

卡波西肉瘤疱疹病毒抑制剂

基本信息

批准号：
8234716
负责人：
Kenneth M Kaye
金额：
$ 4.45万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-27 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234716
关键词：
Binding Biological Assay Biology C-terminal Cell Death Cell Nucleus Cell division Cells Chemicals Cytoplasm DNA DNA Binding DNA Binding Domain DNA Sequence DNA biosynthesis Daughter Elements Ensure Episome Fluorescence Polarization Gene Expression Genes Genetic Transcription Genome Growth Herpesviridae Herpesviridae Infections Histones Human Human Herpesvirus 4 Human Herpesvirus 8 In Vitro Investigation Kaposi Sarcoma Lymphoma Maintenance Malignant Neoplasms Mitotic Chromosome Modeling Molecular N-terminal Nucleic Acid Regulatory Sequences Oncogenic Viruses Papillomavirus Pathway interactions Plasmids Prevention Prevention strategy Reagent Regulation Role Structure Terminal Repeat Sequences Testing Therapeutic Validation Viral Viral Genome Virus Virus Diseases Work antigen binding cell growth daughter cell effusion high throughput screening improved in vivo inhibitor/antagonist innovation latency-associated nuclear antigen latent infection miniaturize neoplastic cell prevent promoter public health relevance sarcoma segregation small molecule tool tumor viral DNA

项目摘要

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi's sarcoma and primary effusion lymphoma. KSHV latently infects tumor cells. In latent infection, the viral genome persists in tumor cells as a multiple copy, extrachromosomal plasmid (episome). To persist, the viral genome must replicate with each cell division and then segregate to daughter cell nuclei. KSHV latency-associated nuclear antigen (LANA) ensures these tasks are performed and that efficient transfer of the viral DNA to progeny tumor cells occurs. LANA tethers KSHV DNA to mitotic chromosomes to allow efficient segregation of viral episomes to daughter cell nuclei. C-terminal LANA self-associates to bind specific DNA sequence in the KSHV terminal repeat (TR) elements. This C-terminal LANA DNA binding is essential for KSHV DNA replication, tethering to mitotic chromosomes, and episome persistence. Currently, there are no small molecule inhibitors for LANA. Since LANA is critical for KSHV latent infection, chemical probes which block the essential LANA binding to the TR DNA would serve as extremely useful reagents to investigate LANA and KSHV biology. Such inhibitory small molecules would be of potential therapeutic benefit since tumor cell persistence is dependent on KSHV infection. This work will develop a robust, reproducible, and miniaturized fluorescence polarization (FP) assay for a high throughput screen for small molecules that inhibit KSHV LANA binding to its DNA recognition sequence. Pilot screens using the FP assay will validate the assay prior to high throughput screening. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma-associated herpesvirus has a causative role in certain human cancers. This work will develop tests to identify compounds that can be used to study this virus. These compounds may potentially be used to prevent and treat the cancers this virus causes.

描述（由申请人提供）：Kaposi的肉瘤相关疱疹病毒（KSHV）在Kaposi的肉瘤和一级积液淋巴瘤中具有病因。 KSHV潜在地感染肿瘤细胞。在潜在感染中，病毒基因组在肿瘤细胞中一直持续为多拷贝，即外染色体外质粒（ecipome）。为了持续存在，病毒基因组必须在每个细胞分裂中复制，然后分离为子细胞核。 KSHV潜伏期相关的核抗原（LANA）确保执行这些任务，并将病毒DNA向后代肿瘤细胞的有效转移。 Lana将KSHV DNA转化为有丝分裂染色体，以使病毒发作有效分离为子细胞核。 C末端LANA自求解以结合KSHV末端重复（TR）元素中的特定DNA序列。这种C末端LANA DNA结合对于KSHV DNA复制，绑定到有丝分裂染色体和依恋症是必不可少的。目前，LANA没有小分子抑制剂。由于LANA对于KSHV潜在感染至关重要，因此阻断与TR DNA的必需LANA结合的化学探针将作为研究LANA和KSHV生物学的极有用的试剂。这种抑制性小分子将具有潜在的治疗益处，因为肿瘤细胞的持久性取决于KSHV感染。这项工作将开发出强大的，可重现的和微型化的荧光极化（FP）测定法，用于高吞吐量屏幕，用于抑制KSHV LANA与其DNA识别序列的小分子。使用FP测定法将在高吞吐量筛选之前验证该测定法。公共卫生相关性：Kaposi与肉瘤相关的疱疹病毒在某些人类癌症中起因作用。这项工作将开发测试以识别可用于研究该病毒的化合物。这些化合物可能有可能用于预防和治疗这种病毒原因。