Small Molecule Inhibitors of EBV Latency

EBV潜伏期的小分子抑制剂

基本信息

  • 批准号:
    6656740
  • 负责人:
  • 金额:
    $ 19.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-04-01 至 2005-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The objective of the proposed research is to evaluate the antiviral potential of synthetic small molecule compounds known as polyamides for their ability to specifically inhibit Epstein-Barr virus (EBV) latency-gene expression and functions that contribute to EBV-associated lymphomas and lymphoproliferative disease in immune compromised individuals. Polyamides bind within the minor groove of a DNA double helix in a sequence-specific manner with affinities comparable to many sequence-specific DNA-binding proteins. Consequently, these compounds have the ability to compete with proteins (e.g., transcription factors) that target the same or an overlapping binding site within dsDNA, thus disrupting their function. This and the generally favorable pharmacological properties of polyamides make them attractive as antiviral drugs to inhibit the expression or DNA-binding functions of viral proteins critical for pathogenesis. Such agents targeting latent EBV infection are particularly attractive, since current anti-herpesvirus drugs are designed to inhibit virus replication and are ineffective against the latent or transforming form of EBV infection. Three specific aims are proposed. Under Aim 1 we will evaluate the in vivo inhibitory potential of hairpin polyamides designed to target EBV latency gene promoters and the viral origin of DNA replication, oriP. Specifically, we will seek to block transcription of the EBV genes encoding the essential genome maintenance protein EBNA-1 and the oncoprotein LMP-1 by inhibition of the binding of transcription factors to critical cis-regulatory elements of the EBNA- 1 and LMP- 1 promoters. Additionally, we will test whether polyamides designed to inhibit binding of EBNA- 1 to oriP are capable of enforcing loss of the EBV genome from EBV-positive lymphoma cells. Under Aim 2 we propose to develop DNA-binding and whole-cell reporter based assays that are compatible with high throughput screening of chemical libraries so that the most effective inhibitors of EBNA-1 binding to oriP and of EBNA-1 and LMP-1 expression can be identified. Under Aim 3, we will take a combinatorial approach to identify polyamide inhibitors of EBNA-1 DNA-binding and of EBNA-1 and LMP-1 expression. Specifically, we propose to generate a combinatorial library of polyamide-based compounds that will be screened, using the bioassays developed under Aim 2, to identify lead compounds with anti-EBV properties. By taking the complementing approaches of rational and combinatorial drug design in Aims 1 and 3, respectively, we hope to effectively evaluate the anti-EBV potential of these compounds, and identify lead compounds with potential therapeutic value.
描述(由申请人提供):

项目成果

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{{ truncateString('JEFFERY T SAMPLE', 18)}}的其他基金

Viral Long Noncoding RNA Functions in Epstein-Barr Virus Infection
病毒长非编码 RNA 在 Epstein-Barr 病毒感染中的功能
  • 批准号:
    8806522
  • 财政年份:
    2014
  • 资助金额:
    $ 19.9万
  • 项目类别:
Viral Long Noncoding RNA Functions in Epstein-Barr Virus Infection
病毒长非编码 RNA 在 Epstein-Barr 病毒感染中的功能
  • 批准号:
    8659714
  • 财政年份:
    2014
  • 资助金额:
    $ 19.9万
  • 项目类别:
Viral Long Noncoding RNA Functions in Epstein-Barr Virus Infection
病毒长非编码 RNA 在 Epstein-Barr 病毒感染中的功能
  • 批准号:
    9017925
  • 财政年份:
    2014
  • 资助金额:
    $ 19.9万
  • 项目类别:
Mechanisms of Epstein-Barr Virus Persistence
EB 病毒持续存在的机制
  • 批准号:
    8728373
  • 财政年份:
    2013
  • 资助金额:
    $ 19.9万
  • 项目类别:
Mechanisms of Gene Regulation by EBV EBNA-1 Protein
EBV EBNA-1蛋白的基因调控机制
  • 批准号:
    7621316
  • 财政年份:
    2009
  • 资助金额:
    $ 19.9万
  • 项目类别:
Mechanisms of Gene Regulation by EBV EBNA-1 Protein
EBV EBNA-1蛋白的基因调控机制
  • 批准号:
    7847575
  • 财政年份:
    2009
  • 资助金额:
    $ 19.9万
  • 项目类别:
Mechanisms of Gene Regulation by EBV EBNA-1 Protein
EBV EBNA-1蛋白的基因调控机制
  • 批准号:
    7681398
  • 财政年份:
    2008
  • 资助金额:
    $ 19.9万
  • 项目类别:
Small Molecule Inhibitors of EBV Latency
EBV潜伏期的小分子抑制剂
  • 批准号:
    6719551
  • 财政年份:
    2003
  • 资助金额:
    $ 19.9万
  • 项目类别:
Murine Model of Gammaherpesvirus Latency
伽马疱疹病毒潜伏期小鼠模型
  • 批准号:
    6514926
  • 财政年份:
    2001
  • 资助金额:
    $ 19.9万
  • 项目类别:
Murine Model of Gammaherpesvirus Latency
伽马疱疹病毒潜伏期小鼠模型
  • 批准号:
    6633947
  • 财政年份:
    2001
  • 资助金额:
    $ 19.9万
  • 项目类别:

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