PURINE ANALOG ANTIMYCOBACTERIAL DRUG DEVELOPMENT

嘌呤类似物抗真菌药物的开发

• 批准号: 2797353
• 负责人: WILLIAM B PARKER
• 金额: $ 37.74万
• 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 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2797353
• 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

Through the NIAID-sponsored Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF), we have identified numerous anti-Mycobacterium tuberculosis (M. tb) lead compounds that are structurally similar to purine bases and nucleosides. The goal of this grant proposal is to understand the metabolism of these agents in M. tb and human cells in order to identify the basis for their selective activity. These studies should lead to a thorough understanding of the substrate characteristics of key M. tb purine salvage enzymes. Much is known about the substrate requirements of human enzymes involved in purine metabolism, because of the considerable effort to develop antitumor nucleoside analogs. However, very little is known about the substrate characteristics of purine metabolizing enzymes in M. tb. The proposed studies should remedy this deficiency, and the information gained will be useful in the rational design and development of new agents based on metabolic differences in purine metabolism between humans and M. tb. In our preliminary data we have identified a metabolic difference between M. tb and human purine metabolism that could be involved in the selective activation in M. tb of certain adenosine analogs. However, further work is necessary to completely characterize the mechanism of action of these and other agents. The proposed specific aims to accomplish these goals are: (1) characterization of the metabolism and mechanism of action of adenosine analogs in intact M. tb; (2) isolation and characterization of purine salvage enzymes from M. tb and human sources; (3) design and synthesis of adenosine analogs selective for M. tb; (4) design and synthesis of a combinatorial library of 2 and 6-substituted purities; (5) preliminary biochemical evaluation of compounds synthesized in aim 4; and (6) evaluation of compounds for anti-M. tb activity and toxicity.

通过 NIAID 赞助的结核病抗菌药物获取和协调设施 (TAACF)，我们已经鉴定出许多在结构上与嘌呤碱基和核苷相似的抗结核分枝杆菌 (M. tb) 先导化合物。该拨款提案的目标是了解这些药物在结核分枝杆菌和人类细胞中的代谢，以确定其选择性活性的基础。 这些研究应该有助于彻底了解结核分枝杆菌嘌呤补救酶的底物特征。 由于开发抗肿瘤核苷类似物的巨大努力，人们对嘌呤代谢中涉及的人类酶的底物需求了解很多。 然而，人们对结核分枝杆菌嘌呤代谢酶的底物特性知之甚少。 拟议的研究应该弥补这一缺陷，并且所获得的信息将有助于根据人类和结核分枝杆菌之间的嘌呤代谢差异合理设计和开发新药物。 在我们的初步数据中，我们已经确定了结核分枝杆菌和人类嘌呤代谢之间的代谢差异，这可能与结核分枝杆菌中某些腺苷类似物的选择性激活有关。 然而，需要进一步的工作来完全表征这些药物和其他药物的作用机制。为实现这些目标而提出的具体目标是：（1）完整结核分枝杆菌中腺苷类似物的代谢和作用机制的表征； (2) 结核分枝杆菌和人类来源的嘌呤补救酶的分离和表征； (3)针对结核分枝杆菌选择性的腺苷类似物的设计与合成； (4) 2位和6位取代纯度的组合文库的设计和合成； (5)目标4合成的化合物的初步生化评价； (6)化合物抗M的评价。结核菌活性和毒性。