Developing Tuberculosis (TB) Cell Wall Enzyme Drug Targets

开发结核病 (TB) 细胞壁酶药物靶点

基本信息

批准号：
7628547
负责人：
Michael R McNeil
金额：
$ 25.5万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7628547
关键词：
Anabolism Back Biological Biological Assay Cell Wall Cells Characteristics Chemicals Class Commit Data Development Diphosphates Drug Delivery Systems Drug Kinetics Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Figs - dietary Geranyltranstransferase Goals Growth Human Resources In Vitro Inhibitory Concentration 50 Lead Ligase Link Modeling Multiple drug resistant Mycobacteria Tuberculosis Mus Mycobacterium tuberculosis Occupations Pharmaceutical Preparations Pharmacology Principal Investigator Procedures Property Range Reaction Reporting Rhamnose Roentgen Rays Role Running Safety Scheme Screening procedure Standards of Weights and Measures Stress Structure Testing Time Toxic effect Toxicity Tests Transferase Tuberculosis UDP-galactopyranose mutase Wing Work base decaprenyl pyrophosphate synthetase design drug development enzyme structure in vivo inhibitor/antagonist mouse model pre-clinical programs small molecule libraries success synthetic enzyme tuberculosis drugs

Anabolism Back Biological Biological Assay Cell Wall Cells Characteristics Chemicals Class Commit Data Development Diphosphates Drug Delivery Systems Drug Kinetics Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Figs - dietary Geranyltranstransferase Goals Growth Human Resources In Vitro Inhibitory Concentration 50 Lead Ligase Link Modeling Multiple drug resistant Mycobacteria Tuberculosis Mus Mycobacterium tuberculosis Occupations Pharmaceutical Preparations Pharmacology Principal Investigator Procedures Property Range Reaction Reporting Rhamnose Roentgen Rays Role Running Safety Scheme Screening procedure Standards of Weights and Measures Stress Structure Testing Time Toxic effect Toxicity Tests Transferase Tuberculosis UDP-galactopyranose mutase Wing Work base decaprenyl pyrophosphate synthetase design drug development enzyme structure in vivo inhibitor/antagonist mouse model pre-clinical programs small molecule libraries success synthetic enzyme tuberculosis drugs

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项目摘要

In project 3 of this P01, we focus on the development and execution of micro titer plate based enzyme assays for cell wall synthetic enzymes that are required by M. tuberculosis for viability. In the over all P01 a refinement cycle has been developed in which compounds are synthesized by a compound development module and analyzed by a compound analysis module. The biological activities of the compounds are reported to the compound development module and the cycle repeated until leads that are effective against MDR-TB and also effective against TB in mice are produced. One of our tasks in project 3 is to determine IC50's and, as appropriate, Ki's of inhibitors of "cycle ready enzymes" made by the compound development module. At present, these "cycle ready enzymes" include two enzymes involved in the synthesis of dTDP-rhamnose (RmlC and RmlD) and the enzyme UDP-galactopyranose mutase (GIf). By "cycle ready enzyme targets" we mean that they have already had the assays developed for them, crystal structures determined, and inhibitors that can be used as starting points identified by screening chemical libraries. Another major task of project 3 is to develop four additional enzymes so that they can also be targeted by our refinement cycle (i.e. become "cycle ready"). These enzymes are GImU which synthesizes UDP-GIcNAc via two separate reactions, farnesyl diphosphate synthetase, decaprenyl diphosphate synthetase, and various galactofuranosyl transferases. For these enzymes microtiter plate based assays will be developed and chemical libraries screened to identify initial hits. The compound development module will then use this hits to form co-crystals with the enzymes and design and synthesize increasingly more active inhibitors in the context of the refinement cycle.

在该P01的项目3中，我们着重于基于微滴定板的酶测定的开发和执行细胞壁合成酶，这些酶是结核分枝杆菌对生存能力所要求的。在所有P01中，已经开发了一个完善周期，其中化合物由复合开发模块合成并通过化合物分析模块进行分析。该化合物的生物学活性被报告给化合物开发模块，并重复循环，直到产生对MDR-TB有效并有效地对TB产生有效的小鼠。我们在项目3中的任务之一是确定IC50的“循环准备酶”由复合开发模块制造的“循环现成酶”的抑制剂。目前，这些“循环现成酶”包括参与DTDP-RHAMNOSE合成的两种酶（RMLC和RMLD）和酶UDP-半乳吡喃糖突变酶（GIF）。通过“循环准备酶 targets" we mean that they have already had the assays developed for them, crystal structures determined, and inhibitors that can be used as starting points identified by screening chemical libraries. Another major task of project 3 is to develop four additional enzymes so that they can also be targeted by our refinement cycle (i.e. become "cycle ready"). These enzymes are GImU which synthesizes UDP-GIcNAc via two separate reactions, farnesyl开发了这些酶的基于微滴定板的分析酶的二磷酸合成酶，双磷酸二磷酸合成酶和各种纯尿素基的转移酶。