M tuberculosis Membrane Protein Pharmaceutical Targets

结核分枝杆菌膜蛋白药物靶点

• 批准号: 8116483
• 负责人: TIMOTHY A CROSS
• 金额: $ 173.77万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116483
• 关键词: tuberculosis; Membrane; Protein; Pharmaceutical; Targets

DESCRIPTION (provided by applicant): This Proposal is designed to address: 1) an important disease that needs novel drugs - no new drugs for Mycobacterium tuberculosis in 40 years and multi-drug resistant strains as well as extreme drug resistant strains are becoming more common; 2) the lack of structural information for an entire class of drug targets, the membrane proteins - less than 1% of known protein structures are membrane proteins, while 25 to 30% of the genome of most organisms code for membrane proteins - in addition, membrane proteins are more frequently effective drug targets than water-soluble proteins; 3) biological, functional and structural characterization of validated targets - we will characterize only those proteins that are essential for Mtb growth and by targeting membrane proteins, especially the outer membrane proteins, access to the drug targets will not require transport across the bacterial membranes. 4) a gap in screening technology - new small molecule screening technologies based on solution and solid state NMR spectroscopy will be developed specifically for membrane proteins. We have developed an Initial Target List from preliminary results and from literature on essential genes, virulence factors, identification of outer membrane proteins and numerous individual studies on specific potential targets. Some of these proteins are already validated as high potential pharmaceutical targets, these form a Prioritized Target List that will allow all of the Projects and Cores to initiate their efforts on the first day of funding. From biological function (Project 1) to assay development (Project 2) to structural characterization (Project 3) these activities will work closely together. Assays coupled with molecular structure will help establish structure-activity-relationships. Assay development will enable screening against small molecules important for understanding function and potentially important for structural studies. The assays we develop and the ligands we identify will fuel biological experiments designed to understand the life and infection cycle of Mtb. These ligands will be useful as lead compounds in drug discovery, and while this is beyond the scope of this Program, this team will protect the intellectual property for those who may want to pursue the development of drugs for these membrane protein targets. To accomplish these goals a unique team of investigators has been brought together with extensive knowledge of: Mycobacterium tuberculosis, essential Mtb genes, membrane protein physiology, molecular biology, biophysics, and structural characterization. The Program offers access to two of the premier NMR facilities in the world along with their expertise in methodology and technology development, in addition, the Team brings with it unique expression libraries of Mtb membrane proteins and the superb screening facilities and expertise of the Burnham Institute.

描述（由申请人提供）：该提案旨在解决：1）一种需要新药的重要疾病 - 40年内没有新的药物用于结核分枝杆菌的新药，而多药耐药菌株以及极端的耐药菌菌株正在变得越来越普遍； 2）缺乏整个药物靶标的结构信息，膜蛋白 - 少于1％的已知蛋白质结构是膜蛋白，而大多数生物体的基因组的25％至30％的膜蛋白质代码 - 此外，膜蛋白比水溶质蛋白更常见，是更有效的药物靶标； 3）经过验证靶标的生物学，功能和结构表征 - 我们将仅表征那些对MTB生长至关重要的蛋白质，并且通过靶向膜蛋白，尤其是外膜蛋白，访问药物靶标将不需要跨细菌膜的运输。 4）筛选技术的差距 - 基于溶液和固态NMR光谱的新的小分子筛选技术将专门针对膜蛋白开发。我们已经从初步结果和有关基本基因，毒力因子，外膜外蛋白的鉴定以及对特定潜在靶标的大量个人研究的文献中开发了一个初始目标清单。这些蛋白质中的一些已经被证实为高潜在的药物靶标，这些蛋白质构成了优先的目标清单，这将使所有项目和核心都可以在资金的第一天开始努力。从生物功能（项目1）到测定开发（项目2）到结构表征（项目3）这些活动将紧密合作。结合分子结构的测定将有助于建立结构性关系。测定开发将使对了解功能重要的小分子进行筛查，并且对结构研究可能很重要。我们开发的测定法和我们确定的配体将促进旨在了解MTB生命和感染周期的生物学实验。这些配体将作为药物发现中的铅化合物有用，尽管这超出了该计划的范围，但该团队将为那些可能想为这些膜蛋白靶标而开发药物的人保护知识产权。为了实现这些目标，独特的研究人员团队已经汇集了大量了解：结核分枝杆菌，基本MTB基因，膜蛋白质生理学，分子生物学，生物物理学和结构表征。该计划提供了世界上两个主要的NMR设施的访问权限，以及它们在方法论和技术开发方面的专业知识，此外，该团队还带来了MTB膜蛋白的独特表达库以及Burnham Institute的精湛筛查设施和专业知识。