RNA As A Therapeutic Target

RNA作为治疗靶点

基本信息

  • 批准号:
    8142739
  • 负责人:
  • 金额:
    $ 31.27万
  • 依托单位:
  • 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:
    2010-09-13 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Although 26 years has passed since HIV-1 was identified as the causative agent for AIDS, the percentage of people living with HIV has steadily increased as new infections occur each year and as HIV treatments extend life. An estimated 33 million people were living with HIV in 2007. Most of the current drugs in use for the treatment of AIDS work by combination targeting of the enzymatic activities of the HIV reverse transcriptase and/or protease (HAART, highly active anti-retroviral therapy) and/or gp41. These treatments remain expensive and are often not well- tolerated by patients. Because of the emergence of drug-resistant virus that commonly occurs as the result of classical HIV treatment, there remains a great need to continue the search for alternative therapies that target other essential viral activities. Thus, the development of new drugs with novel mode of action is of utmost urgency. We propose to develop inhibitors of protein-RNA interactions that are absolutely essential for the HIV life cycle-excellent targets widely recognized by the community. TAR and RRE RNAs are well-conserved noncoding sequences in the viral genome with defined targetable structures. Targeting these RNA structures is attractive because the affect virus-specific interactions that could potentially lead to specific inhibition of viral replication, with possibly minimal side effects on other cellular functions. Additionally, this strategy can result in a lower incidence of drug resistance since the regulation of HIV-1 transcription requires the interplay of both viral and cellular components. We have recently reported that branched peptides are good selective ligands for HIV-1 TAR. We propose to carry-out the screening of combinatorial libraries of short branched peptides. This is accomplished with specific aim 1, wherein a larger library of diversified branched peptides and borono-branched peptides is synthesized. Because the major challenge in targeting RNA is imparting selectivity to a particular sequence/structure, a highly stringent screening assay is necessary. This is also addressed in Aim 1. We recognize that during a high throughput screening assay, false positives are possible and that an RNA binder does not necessarily indicate perturbation of the desired protein/RNA interaction. In aim 2, we use a series of cell based assays to test the inhibitory activities of hit branched peptides against HIV-1 Tat/TAR and Rev/RRE interactions. Additionally, we investigate the selectivity as well as possible cytotoxicity of branched peptide inhibitors. PUBLIC HEALTH RELEVANCE: The proposed research aims to discover and develop medium-sized molecules that selectively inhibit the interaction of protein-RNA interactions that are absolutely essential for HIV-1 viral replication. If successful, these molecules will be the next generation drugs with novel mode of action as anti-HIV therapy.
描述(由申请人提供):虽然自HIV-1被确定为艾滋病的病原体以来已经过去了26年,但随着每年新感染的发生和艾滋病毒治疗延长寿命,艾滋病毒感染者的比例稳步上升。2007年估计有3 300万人感染艾滋病毒。目前用于治疗AIDS的大多数药物通过联合靶向HIV逆转录酶和/或蛋白酶(HAART,高效抗逆转录病毒疗法)和/或gp 41的酶活性而起作用。这些治疗仍然昂贵,并且患者通常不能很好地耐受。由于耐药病毒的出现通常是经典HIV治疗的结果,因此仍然非常需要继续寻找针对其他基本病毒活性的替代疗法。因此,开发具有新作用模式的新药迫在眉睫。我们建议开发蛋白质-RNA相互作用的抑制剂,这对HIV生命周期是绝对必要的,是被社会广泛认可的优秀靶点。TAR和RRE RNA是病毒基因组中高度保守的非编码序列,具有确定的靶向结构。靶向这些RNA结构是有吸引力的,因为它们影响病毒特异性相互作用,可能导致病毒复制的特异性抑制,对其他细胞功能的副作用可能最小。此外,这种策略可以降低耐药性的发生率,因为HIV-1转录的调节需要病毒和细胞成分的相互作用。我们最近报道了分支肽是HIV-1 TAR的良好选择性配体。我们建议进行筛选短分支肽的组合文库。这是通过具体目标1来实现的,其中合成了更大的多样化分支肽和硼分支肽库。由于靶向RNA的主要挑战是赋予特定序列/结构选择性,因此需要高度严格的筛选测定。目标1也涉及这一点。我们认识到,在高通量筛选测定期间,假阳性是可能的,并且RNA结合剂不一定指示所需蛋白质/RNA相互作用的扰动。在目标2中,我们使用一系列基于细胞的测定来测试命中分支肽对HIV-1达特/TAR和Rev/RRE相互作用的抑制活性。此外,我们调查的选择性,以及可能的细胞毒性的支链肽抑制剂。 公共卫生相关性:这项研究的目的是发现和开发中等大小的分子,选择性地抑制蛋白质-RNA相互作用的相互作用,这对HIV-1病毒复制是绝对必要的。如果成功的话,这些分子将成为下一代具有新作用模式的抗HIV治疗药物。

项目成果

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Webster L Santos其他文献

Webster L Santos的其他文献

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{{ truncateString('Webster L Santos', 18)}}的其他基金

SPNS2 inhibitors as renal fibrosis therapy
SPNS2 抑制剂作为肾纤维化治疗
  • 批准号:
    10759681
  • 财政年份:
    2023
  • 资助金额:
    $ 31.27万
  • 项目类别:
Therapeutic Mitochondrial Uncouplers
治疗性线粒体解偶联剂
  • 批准号:
    10185467
  • 财政年份:
    2021
  • 资助金额:
    $ 31.27万
  • 项目类别:
Therapeutic Mitochondrial Uncouplers
治疗性线粒体解偶联剂
  • 批准号:
    10398220
  • 财政年份:
    2021
  • 资助金额:
    $ 31.27万
  • 项目类别:
Therapeutic Mitochondrial Uncouplers
治疗性线粒体解偶联剂
  • 批准号:
    10608112
  • 财政年份:
    2021
  • 资助金额:
    $ 31.27万
  • 项目类别:
RNA As A Therapeutic Target
RNA作为治疗靶点
  • 批准号:
    7930377
  • 财政年份:
    2010
  • 资助金额:
    $ 31.27万
  • 项目类别:
RNA As A Therapeutic Target
RNA作为治疗靶点
  • 批准号:
    8325074
  • 财政年份:
    2010
  • 资助金额:
    $ 31.27万
  • 项目类别:
RNA As A Therapeutic Target
RNA作为治疗靶点
  • 批准号:
    8537941
  • 财政年份:
    2010
  • 资助金额:
    $ 31.27万
  • 项目类别:
RNA As A Therapeutic Target
RNA 作为治疗靶点
  • 批准号:
    8725685
  • 财政年份:
    2010
  • 资助金额:
    $ 31.27万
  • 项目类别:
Peptide Morphing: Rational Design of Separase Inhibitors
肽变形:分离酶抑制剂的合理设计
  • 批准号:
    6585224
  • 财政年份:
    2003
  • 资助金额:
    $ 31.27万
  • 项目类别:
Peptide Morphing: Rational Design of Separase Inhibitors
肽变形:分离酶抑制剂的合理设计
  • 批准号:
    6747260
  • 财政年份:
    2003
  • 资助金额:
    $ 31.27万
  • 项目类别:

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