Purine Analog Anti-Mycobacterial Drug Development

嘌呤类似物抗分枝杆菌药物开发

• 批准号: 7012750
• 负责人: WILLIAM B PARKER
• 金额: $ 47.85万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012750
• 关键词: Mycobacterium tuberculosis; adenine analog; adenosine; antitubercular agents; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; enzyme substrate; nucleoside analog; purine /pyrimidine metabolism

DESCRIPTION (provided by applicant): Through the NIAID-sponsored Tuberculosis Anti-microbial Acquisition and Coordinating Facility (TAACF), we have identified numerous anti-Mycobacterium tuberculosis lead compounds, which are structurally similar to purine bases and nucleosides. In the current grant period (1999 to 2003) we have (1) synthesized many new compounds and evaluated them for activity against M. tb, (2) characterized the biochemical pharmacology of one of the lead compounds (2-methyladenosine), and (3) begun the characterization of the enzymes involved in purine salvage in M. tb. In the new grant proposal we plan to continue these studies to further our understanding of the enzymes involved in the purine salvage pathway in M. tb and to design and synthesize new agents with selective activity against M. tb. Much is known about the substrate requirements of human enzymes involved in purine salvage, because of the considerable effort to develop nucleoside analogs for the treatment of cancer and viral diseases. However, very little is currently known about the substrate characteristics of these enzymes in M. tb. We have identified 3 purine salvage enzymes that are expressed in M. tb that could be exploited in the development of new selective anti-/W. tb agents. Two of these enzymes (adenosine cleavage and guanosine kinase) are not expressed in human cells and we have recently shown that the third enzyme (adenosine kinase) has unique characteristics that could also be used for selective activation of nucleoside analogs. The biochemical and genetic characterization of these enzymes should provide valuable information that will be useful in the rational design and development of new agents based on metabolic differences in purine metabolism between humans and M. tb. The proposed specific aims to accomplish the goals of this grant proposal are: (1) identification, cloning, expression, and purification of M. tb adenosine cleavage and guanosine kinase activities; (2) biochemical characterization of M. tb adenosine kinase, adenosine cleavage, and guanosine kinase activities; (3) metabolic studies with new agents that have potent and selective anti-M. tb activity; and (4) design and synthesis of purine and purine nucleoside analogs with selective activity against M. tb.

描述（由申请人提供）： 通过 NIAID 赞助的结核病抗微生物获取和协调设施 (TAACF)，我们已经鉴定出许多抗结核分枝杆菌先导化合物，它们在结构上与嘌呤碱基和核苷相似。在目前的资助期内（1999年至2003年），我们（1）合成了许多新化合物并评估了它们对结核分枝杆菌的活性，（2）表征了一种主要化合物（2-甲基腺苷）的生化药理学，以及（ 3) 开始表征结核分枝杆菌中参与嘌呤回收的酶。在新的资助提案中，我们计划继续这些研究，以进一步了解结核分枝杆菌嘌呤挽救途径中涉及的酶，并设计和合成具有针对结核分枝杆菌的选择性活性的新药物。由于人们在开发用于治疗癌症和病毒性疾病的核苷类似物方面付出了巨大努力，因此人们对参与嘌呤回收的人类酶的底物要求了解很多。然而，目前对结核分枝杆菌中这些酶的底物特性知之甚少。我们已经鉴定出 3 种在 M. tb 中表达的嘌呤补救酶，可用于开发新的选择性抗/W。结核病制剂。其中两种酶（腺苷裂解和鸟苷激酶）在人体细胞中不表达，我们最近表明第三种酶（腺苷激酶）具有独特的特性，也可用于选择性激活核苷类似物。这些酶的生化和遗传特征应该提供有价值的信息，这些信息将有助于根据人类和结核分枝杆菌之间嘌呤代谢的代谢差异合理设计和开发新药物。 为实现本拨款提案的目标而提出的具体目标是：（1）结核分枝杆菌腺苷裂解和鸟苷激酶活性的鉴定、克隆、表达和纯化； (2)结核分枝杆菌腺苷激酶、腺苷裂解和鸟苷激酶活性的生化特征； (3) 使用具有有效和选择性抗支原体的新药物进行代谢研究。结核病活动； (4)设计和合成对结核分枝杆菌具有选择性活性的嘌呤和嘌呤核苷类似物。