Structure-Based Development of nonnucleoside anti-HIV-1 RT Drugs

非核苷类抗 HIV-1 RT 药物的基于结构的开发

基本信息

项目摘要

DESCRIPTION (provided by applicant): HIV-1 RT is a key enzyme responsible for viral replication and subsequent perpetuation of viral infection. Hence, it has been the primary target for therapeutic intervention against HIV-1 infection. However, rapid emergence of drug-resistant viral strains harboring enzymatically-active mutant RT with reduced drug-sensitivity has frustrated all efforts to control the spread of HIV-1 infection. The mechanism of resistance to nucleoside inhibitors seems to be quite complex since a number of mutational sites do not cluster around the putative dNTP-binding pocket in the polymerase cleft. However, for nonnucleoside RT inhibitors (NNRTIs), a common hydrophobic binding region is seen in the crystal structures of RT liganded with these inhibitors. The side chains of a number of hydrophobic residues located in the fingers, palm and thumb subdomains in the p66 subunit converge to form a hydrophobic NNRTI binding pocket. Any mutational change in these hydrophobic residues reduces the drug-sensitivity due to alteration in the NNRTI-binding pocket. Our proposal seeks to address this problem by developing a group of new NNRTIs which are effective against both the wild type and common drug-resistant variants of HIV-1 RT. Using a combination of structure-based molecular modeling and in vitro assays, we have selected four distinct lead compounds from a large repertoire of compounds displaying inhibitory activity against both wild type and mutant RT. We plan to further modify these lead compounds by a structure-based design strategy to improve their inhibitory potential followed by synthesis and in vitro anti-HIV-1 RT screening. PUBLIC HELATH RELEVANCE: The major focus of this proposal is to develop a new class of NNRTIs that is equally effective against both the wild type and drug-resistant variants of HIV-1 RT. We selected four nonnucleoside lead compounds from a large repertoire of compounds based on structure-based modeling and in vitro anti- RT activity against both the wild type HIV-1 RT and drug-resistant RT mutants. These initial lead compounds will be modified to further enhance their anti-RT activity.
描述(由申请人提供):HIV-1 RT是负责病毒复制和随后病毒感染延续的关键酶。因此,它一直是针对HIV-1感染的治疗干预的主要目标。然而,快速出现的耐药病毒毒株携带酶活性突变RT,药物敏感性降低,使所有控制HIV-1感染传播的努力受挫。对核苷抑制剂的耐药机制似乎相当复杂,因为许多突变位点并不聚集在聚合酶间隙中假定的dntp结合口袋周围。然而,对于非核苷类RT抑制剂(NNRTIs),在与这些抑制剂配体的RT的晶体结构中可以看到一个常见的疏水结合区。位于p66亚基的手指、手掌和拇指亚结构域的一些疏水残基侧链会聚形成疏水NNRTI结合袋。由于nnrti结合口袋的改变,这些疏水残基的任何突变都会降低药物敏感性。我们的建议旨在通过开发一组新的nnrti来解决这个问题,这些nnrti对野生型和常见的HIV-1 rt耐药变体都有效。我们从大量对野生型和突变型RT均具有抑制活性的化合物中选择了四种不同的先导化合物。我们计划通过基于结构的设计策略进一步修饰这些先导化合物,以提高其抑制潜力,随后进行合成和体外抗hiv -1 RT筛选。

项目成果

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Virendra Nath PANDEY其他文献

Virendra Nath PANDEY的其他文献

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{{ truncateString('Virendra Nath PANDEY', 18)}}的其他基金

Implication of RNase H domain on dimer stability and drug sensitivity of HIV-1 RT
RNase H 结构域对 HIV-1 RT 二聚体稳定性和药物敏感性的影响
  • 批准号:
    8707365
  • 财政年份:
    2013
  • 资助金额:
    $ 23.62万
  • 项目类别:
Implication of RNase H domain on dimer stability and drug sensitivity of HIV-1 RT
RNase H 结构域对 HIV-1 RT 二聚体稳定性和药物敏感性的影响
  • 批准号:
    8541412
  • 财政年份:
    2013
  • 资助金额:
    $ 23.62万
  • 项目类别:
FUSE Binding Protein As a Cellular Effector of HCV Replication
FUSE 结合蛋白作为 HCV 复制的细胞效应子
  • 批准号:
    7788343
  • 财政年份:
    2010
  • 资助金额:
    $ 23.62万
  • 项目类别:
FUSE Binding Protein As a Cellular Effector of HCV Replication
FUSE 结合蛋白作为 HCV 复制的细胞效应子
  • 批准号:
    8077981
  • 财政年份:
    2010
  • 资助金额:
    $ 23.62万
  • 项目类别:
Proteomics of HCV Replication Complex
HCV 复制复合物的蛋白质组学
  • 批准号:
    7828015
  • 财政年份:
    2009
  • 资助金额:
    $ 23.62万
  • 项目类别:
Proteomics of HCV Replication Complex
HCV 复制复合物的蛋白质组学
  • 批准号:
    7385667
  • 财政年份:
    2009
  • 资助金额:
    $ 23.62万
  • 项目类别:
Structure-Based Development of nonnucleoside anti-HIV-1 RT Drugs
非核苷类抗 HIV-1 RT 药物的基于结构的开发
  • 批准号:
    7495273
  • 财政年份:
    2009
  • 资助金额:
    $ 23.62万
  • 项目类别:
Genome Targeted Inhibitors of Retroviruses
逆转录病毒基因组靶向抑制剂
  • 批准号:
    6842205
  • 财政年份:
    1999
  • 资助金额:
    $ 23.62万
  • 项目类别:
Genome Targeted Inhibitors of Retroviruses
逆转录病毒基因组靶向抑制剂
  • 批准号:
    7010743
  • 财政年份:
    1999
  • 资助金额:
    $ 23.62万
  • 项目类别:
Genome Targeted Inhibitors of Retroviruses
逆转录病毒基因组靶向抑制剂
  • 批准号:
    7173294
  • 财政年份:
    1999
  • 资助金额:
    $ 23.62万
  • 项目类别:

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