ADENOSINE KINASE TARGET FOR CHEMOTHERAPY IN TGONDII

TGONDII 化疗中的腺苷激酶靶点

• 批准号: 2887719
• 负责人: Mahmoud H el Kouni
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887719
• 关键词: Toxoplasma gondii; adenosine kinase; antiprotozoal agents; drug screening /evaluation; enzyme activity; enzyme inhibitors; inosine; laboratory mouse; microorganism culture; microorganism genetics; molecular cloning; nonhuman therapy evaluation; parasitic disease chemotherapy; pharmacokinetics; purine analog; recombinant proteins; toxoplasmosis

DESCRIPTION (Adapted from the Applicant's Abstract): One feature of the metabolic pathway of T. gondii which distinguishes it form its human host is its inability to synthesize purine nucleotides de novo. Therefore, these organisms rely on the purine salvage pathways for their supply of purine nucleotides. There are unique features of purine metabolism in T. gondii which render the purine salvage pathways suitable targets for chemotherapy. T. gondii, unlike their mammalian hosts, predominantly salvage their purine precursors via adenosine kinase. On the basis of Dr. el Kouni's detailed structure-activity relationship studies on T. gondii adenosine kinase activity, he has identified a group of compounds, the 6-substituted 9-beta-D-ribofuranosylpurines, as potentially good substrates for this enzyme. One of these compounds, NBMPR, is phosphorylated by the parasite adenosine kinase and are also toxic against T. gondii. Furthermore, in collaboration with Dr. David Roos, the T. gondii adenosine kinase gene was successfully cloned to provide a potentially stable source of this enzyme for further studies. The overall goal of these studies is to exploit the differences between host and parasite adenosine kinases for the development of chemotherapeutic agents against toxoplasmosis. There are three specific aims in this proposal: (1) Overexpress a construct o the recently cloned T. gondii adenosine kinase gene to provide a stable source of this enzyme and to purify and characterize the cloned enzyme for drug screening and design; (2) determine the mechanism of selective toxicity of the 6-substituted-9-beta-D ribofuranosylpurines in T. gondii; (3) evaluate active compounds as potential antitoxoplasmosis agents in vitro and in vivo.

描述（改编自申请人的摘要）： T. gondii的代谢途径区分它形成其人类宿主的是 它无法合成从头开始的嘌呤核苷酸。因此，这些 有机体依靠嘌呤拯救途径来供应嘌呤 核苷酸。 T. gondii中有嘌呤代谢的独特特征 这使嘌呤打捞途径适合化学疗法。 T. Gondii，与他们的哺乳动物宿主不同，主要挽救他们的嘌呤 通过腺苷激酶的前体。根据El Kouni博士的详细 弓形虫腺苷激酶的结构活性关系研究 活动，他已经确定了一组化合物，该化合物是6个取代的 9-beta-d-核呋喃糖基嘌呤，作为可能的良好底物 酶。这些化合物之一NBMPR被寄生虫磷酸化 腺苷激酶，也有毒，抗gondii。此外，在 与大卫·鲁斯（David Roos）博士合作，T。gondii腺苷激酶基因是 成功克隆以提供该酶的潜在稳定来源 进行进一步研究。这些研究的总体目标是利用 宿主和寄生虫腺苷激酶之间的差异 针对弓形虫病的化学治疗剂。 该提案中有三​​个具体目标：（1）过表达构造 o最近克隆的T. gondii腺苷激酶基因提供稳定 该酶的来源并纯化和表征克隆的酶 药物筛查和设计； （2）确定选择性毒性的机制 T. gondii中的6-取代-9-beta-d核呋喃糖基嘌呤； （3） 评估活性化合物作为体外潜在的抗毒素剂和 体内。