M TUBERCULOSIS ADENOSINE KINASE AND ANTI-MICROBIAL NUCLEOSIDE ANALOGS

结核分枝杆菌腺苷激酶和抗微生物核苷类似物

• 批准号: 7721206
• 负责人: RONGBAO LI
• 金额: $ 0.37万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721206
• 关键词: Adenosine; Adenosine Kinase; Antimycobacterial Agents; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Enzymes; Funding; Goals; Grant; Infection; Institution; Lead; Morbidity - disease rate; Multi-Drug Resistance; Mycobacterium tuberculosis; Nucleosides; Opportunistic Infections; Pathway interactions; Phosphorylation; Prodrugs; Purines; Reaction; Research; Research Personnel; Resources; Source; Structure; Therapeutic Agents; Tuberculosis; United States National Institutes of Health; analog; antimicrobial; base; enzyme substrate; mortality; nucleoside analog; pathogen; preference; purine; tuberculosis treatment

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis is an opportunistic infection pathogen that causes TB and morbidity and mortality worldwide. The emergence of multi-drug resistance (MDR) strains and the AIDS-associated TB infection has led to a critical need for the development of new and effective therapeutic agents for the TB treatment. Adenosine kinase from M. tuberculosis (Mtb-AK) has recently been identified to be responsible for the bioactivation of a group of nucleoside analogs against M. tuberculosis. Our long-term goal is to develop new antimycobacterial agents by exploiting the specific activation of a nucleoside prodrug by Mtb-AK, a key enzyme in the purine salvage pathway. Our specific aims are: 1). to characterize the crystal structure of Mtb-AK in different forms and to elute the enzyme reaction mechanism involved in adenosine phosphorylation and bioactivation of adenosine analogs in M. tuberculosis. 2) To characterize the structural basis of the enzyme's substrate preferences and the structural features of nucleoside analogs that can be activated more efficiently and selectively by Mtb-AK. 3) To characterize the Mtb-AK complex structures with the lead adenosine analogs and the structural basis for optimization of nucleoside analogs.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 结核分枝杆菌是一种机会性感染病原体，在全世界范围内导致结核病以及发病率和死亡率。多重耐药（MDR）菌株和艾滋病相关结核感染的出现导致迫切需要开发新的有效的结核治疗药物。最近已确定来自结核分枝杆菌的腺苷激酶 (Mtb-AK) 负责一组抗结核分枝杆菌的核苷类似物的生物激活。我们的长期目标是通过利用 Mtb-AK（嘌呤补救途径中的关键酶）对核苷前药的特异性激活来开发新的抗分枝杆菌药物。我们的具体目标是：1）。表征不同形式的 Mtb-AK 晶体结构，并洗脱参与结核分枝杆菌中腺苷磷酸化和腺苷类似物生物活化的酶反应机制。 2) 表征酶底物偏好的结构基础以及可以被Mtb-AK更有效和选择性激活的核苷类似物的结构特征。 3) 表征Mtb-AK与先导腺苷类似物的复合物结构以及核苷类似物优化的结构基础。