M tuberculosis Membrane Protein Pharmaceutical Targets

结核分枝杆菌膜蛋白药物靶点

• 批准号: 8608194
• 负责人: TIMOTHY A CROSS
• 金额: $ 4.52万
• 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/8608194
• 关键词: Address; Biological; Biological Assay; Biological Process; Biophysics; Code; Coupled; Disease; Drug Targeting; Drug resistance; Essential Genes; Expression Library; Funding; Genome; Goals; Growth; Individual; Infection; Institutes; Intellectual Property; Knowledge; Lead; Life; Ligands; Literature; Membrane; Membrane Protein Gene; Membrane Proteins; Methodology; Molecular Biology; Molecular Structure; Multi-Drug Resistance; Mycobacterium tuberculosis; NMR Spectroscopy; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Physiology; Proteins; Research Personnel; Solutions; Structure-Activity Relationship; Technology; Virulence Factors; Water; Work; assay development; base; design; drug development; drug discovery; new technology; novel; programs; protein structure; research study; resistant strain; screening; small molecule; solid state nuclear magnetic resonance; technology development

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（申请人提供）：本提案旨在解决：1）需要新药的重要疾病——结核分枝杆菌40年没有新药，多重耐药菌株以及极端耐药菌株变得越来越普遍; 2) 缺乏整类药物靶点膜蛋白的结构信息——已知蛋白质结构中不到 1% 是膜蛋白，而大多数生物体的基因组中有 25% 至 30% 编码膜蛋白——此外，膜蛋白比水溶性蛋白更常成为有效的药物靶点； 3) 已验证靶标的生物学、功能和结构表征 - 我们将仅表征 Mtb 生长所必需的那些蛋白质，并且通过靶向膜蛋白，特别是外膜蛋白，获得药物靶标将不需要跨细菌膜运输。 4）筛选技术的差距——将专门针对膜蛋白开发基于溶液和固态核磁共振波谱的新型小分子筛选技术。我们根据初步结果和有关基本基因、毒力因子、外膜蛋白鉴定的文献以及针对特定潜在目标的大量单独研究制定了初步目标列表。其中一些蛋白质已经被验证为高潜力的药物靶点，这些形成了优先目标列表，这将使所有项目和核心在资助的第一天就开始努力。从生物功能（项目 1）到测定开发（项目 2）再到结构表征（项目 3），这些活动将紧密结合在一起。与分子结构相结合的测定将有助于建立结构-活性关系。检测方法的开发将能够筛选小分子，这对于理解功能很重要，并且对于结构研究也可能很重要。我们开发的检测方法和我们确定的配体将为旨在了解结核分枝杆菌的生命和感染周期的生物实验提供动力。这些配体将可用作药物发现中的先导化合物，虽然这超出了本计划的范围，但该团队将为那些可能想要开发这些膜蛋白靶点药物的人保护知识产权。为了实现这些目标，我们组建了一个独特的研究团队，他们拥有以下方面的广泛知识：结核分枝杆菌、必需的 Mtb 基因、膜蛋白生理学、分子生物学、生物物理学和结构表征。该计划提供了使用世界上两个顶级 NMR 设施的机会以及他们在方法和技术开发方面的专业知识，此外，该团队还带来了独特的 Mtb 膜蛋白表达库以及伯纳姆研究所的一流筛选设施和专业知识。

项目成果

Organ pathology in the absence of bacteria?

没有细菌时的器官病理学？

• DOI: 10.1093/infdis/jit606
• 发表时间: 2014
• 期刊: The Journal of infectious diseases
• 作者: Jones,ChristopherM;Niederweis,Michael
• 通讯作者: Niederweis,Michael

Mycobacteria, metals, and the macrophage.

• DOI: 10.1111/imr.12265
• 发表时间: 2015-03
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Neyrolles O;Wolschendorf F;Mitra A;Niederweis M
• 通讯作者: Niederweis M

Mycobacterium tuberculosis Rv0899 defines a family of membrane proteins widespread in nitrogen-fixing bacteria.

结核分枝杆菌 Rv0899 定义了广泛存在于固氮细菌中的膜蛋白家族。

• DOI: 10.1002/prot.23151
• 发表时间: 2011
• 期刊: Proteins
• 影响因子: 2.9
• 作者: Marassi,FrancescaM

Mycobacterial Esx-3 requires multiple components for iron acquisition.

分枝杆菌 Esx-3 需要多种成分来获取铁。

• DOI: 10.1128/mbio.01073-14
• 发表时间: 2014
• 期刊: mBio
• 影响因子: 6.4
• 作者: Siegrist,MSloan;Steigedal,Magnus;Ahmad,Rushdy;Mehra,Alka;Dragset,MarteS;Schuster,BrianM;Philips,JenniferA;Carr,StevenA;Rubin,EricJ
• 通讯作者: Rubin,EricJ