STRUCTURAL BIOLOGY OF ENZYMES ACTIVATING PRODRUGS

酶激活前药的结构生物学

基本信息

  • 批准号:
    6313486
  • 负责人:
  • 金额:
    $ 21.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-03-01 至 2004-02-28
  • 项目状态:
    已结题

项目摘要

The long-term goal of this project is to understand the molecular determinants of substrate specificity and the enzymatic mechanism of enzymes involved in the activation of nucleoside prodrugs. Nucleoside prodrugs, major therapeutic agents for the treatment of HIV and cancer, are administered as uncharged nucleoside analogs to achieve effective intracellular concentrations. Once inside the cell, these prodrugs must be phosphorylated by cellular enzymes to become the active drug. Examples are AZT against HIV infections, which is activated by thymidylate kinase, and 6thiopurine, which is activated by guanylate kinase, against cancer. A major limitation to the efficacy of such prodrugs results from their poor activation by the human kinases. We are focusing on two families of nucleoside analogs, those that are activated by thymidylate kinase (TMPK) and those activated by guanylate kinase (GMPK). The specific aims of this proposal are: 1. Delineate the role of conserved active site residues in catalysis and in achieving substrate specificity in the human thymidylate kinase. 2. Determine the effects of 3'-substitutions of TMP analogs on the phosphorylation rate by TMPK. 3. Elucidate the determinants of substrate specificity and the catalytic mechanism of kinases involved in the phosphorylation of guanine-based prodrugs. Our primary technology will include X-ray crystallography, complemented by other biochemical, biophysical and genetic approaches that include steady state kinetics, stopped-flow kinetics, and site-directed mutagenesis. Successful completion of this work will yield detailed information on catalysis and substrate recognition by nucleoside and nucleotides kinases. In addition, the information relating to the phosphoryl transfer reaction, a common and significant reactions in biological systems, will be generated. Collectively, this new information is expected to facilitate the development of new nucleoside prodrugs for the treatment of a spectrum of diseases including AIDS, cancer, and other viral infections.
该项目的长期目标是了解底物特异性的分子决定因素以及参与核苷前药激活的酶的酶促机制。核苷前药,用于治疗HIV和癌症的主要治疗剂,被用作未加成的核苷类似物,以实现有效的细胞内浓度。一旦进入细胞,这些前药必须被细胞酶磷酸化,以成为活性药物。例子是针对HIV感染的AZT,该AZT是由胸苷激酶激活的,而6-硫嘌呤被鸟苷酸激酶激活的癌症,针对癌症。这种前药的疗效的主要局限性是由于人类激酶激活不佳而导致的。我们专注于两个核苷类似物,这些核苷类似物是由胸苷酸酯激酶(TMPK)激活的核苷类似物,以及被鸟苷酸激酶(GMPK)激活的核苷类似物。该提案的具体目的是:1。描述保守活性位点残基在催化和达到人胸苷激酶中底物特异性方面的作用。 2。确定TMP类似物对TMPK的磷酸化速率的3'取消作用的影响。 3。阐明底物特异性的决定因素以及与基于鸟嘌呤的前药磷酸化有关的激酶的催化机制。我们的主要技术将包括X射线晶体学,并由其他生化,生物物理和遗传方法互补,包括稳态动力学,停止流动动力学和定位的诱变。这项工作的成功完成将产生有关核苷和核苷酸激酶的催化和底物识别的详细信息。此外,将产生与磷酸转移反应有关的信息,即生物系统中的常见和重要反应。总的来说,这些新信息有望促进新的核苷前药的发展,以治疗包括艾滋病,癌症和其他病毒感染在内的疾病。

项目成果

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科研奖励数量(0)
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ARNON LAVIE其他文献

ARNON LAVIE的其他文献

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{{ truncateString('ARNON LAVIE', 18)}}的其他基金

Pharmacological and toxicological testing of a novel L-asparaginase
新型L-天冬酰胺酶的药理和毒理测试
  • 批准号:
    10265351
  • 财政年份:
    2019
  • 资助金额:
    $ 21.98万
  • 项目类别:
Pharmacological and toxicological testing of a novel L-asparaginase
新型L-天冬酰胺酶的药理和毒理测试
  • 批准号:
    9898149
  • 财政年份:
    2019
  • 资助金额:
    $ 21.98万
  • 项目类别:
Pharmacological and toxicological testing of a novel L-asparaginase
新型L-天冬酰胺酶的药理和毒理测试
  • 批准号:
    10454879
  • 财政年份:
    2019
  • 资助金额:
    $ 21.98万
  • 项目类别:
Expanding the efficacy of asparaginase to solid tumors
将天冬酰胺酶的功效扩展到实体瘤
  • 批准号:
    10582953
  • 财政年份:
    2013
  • 资助金额:
    $ 21.98万
  • 项目类别:
Development of Human Asparaginase for Cancer Therapy
用于癌症治疗的人天冬酰胺酶的开发
  • 批准号:
    8437479
  • 财政年份:
    2013
  • 资助金额:
    $ 21.98万
  • 项目类别:
Development of Human Asparaginase for Cancer Therapy
用于癌症治疗的人天冬酰胺酶的开发
  • 批准号:
    8803343
  • 财政年份:
    2013
  • 资助金额:
    $ 21.98万
  • 项目类别:
Development of Human Asparaginase for Cancer Therapy
用于癌症治疗的人天冬酰胺酶的开发
  • 批准号:
    9344830
  • 财政年份:
    2013
  • 资助金额:
    $ 21.98万
  • 项目类别:
Development of Human Asparaginase for Cancer Therapy
用于癌症治疗的人天冬酰胺酶的开发
  • 批准号:
    8660226
  • 财政年份:
    2013
  • 资助金额:
    $ 21.98万
  • 项目类别:
Molecular imaging of cell-based therapeutics using an engineered human enzyme.
使用工程人类酶对基于细胞的疗法进行分子成像。
  • 批准号:
    8161788
  • 财政年份:
    2011
  • 资助金额:
    $ 21.98万
  • 项目类别:
Molecular imaging of cell-based therapeutics using an engineered human enzyme.
使用工程人类酶对基于细胞的疗法进行分子成像。
  • 批准号:
    8497686
  • 财政年份:
    2011
  • 资助金额:
    $ 21.98万
  • 项目类别:

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  • 批准号:
    7254451
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    2006
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  • 批准号:
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  • 批准号:
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  • 财政年份:
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    $ 21.98万
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S1P信号在外科心脏重塑中的作用
  • 批准号:
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