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机构（TAACF），我们已经鉴定出许多抗结核分枝杆菌（M。tb）结构上类似于嘌呤碱基和核苷的先导化合物。这项资助提案的目的是了解这些药物在M.结核和人类细胞，以确定其选择性活性的基础。 这些研究将有助于对关键M.结核病嘌呤补救酶。 由于开发抗肿瘤核苷类似物的大量努力，对嘌呤代谢中涉及的人类酶的底物需求已经有了很多了解。 然而，对M. TB. 拟议的研究应弥补这一不足，所获得的信息将有助于基于人类和M之间嘌呤代谢的代谢差异合理设计和开发新药物。TB. 在我们的初步数据中，我们已经确定了M.结核分枝杆菌和人嘌呤代谢可能参与M.某些腺苷类似物的TB。 然而，需要进一步的工作来完全表征这些和其他代理的作用机制。为实现这些目标，我们提出的具体目标是：（1）腺苷类似物在完整M.（2）M. tb嘌呤补救酶的分离与鉴定。结核菌和人源的腺苷类似物的设计与合成;结核病;（4）2和6-取代纯度的组合文库的设计和合成;（5）目的4中合成的化合物的初步生物化学评价;和（6）化合物抗M.结核病活性和毒性。