Fragment based inhibitor discovery of the MEP pathway in infectious organisms.

基于片段的感染性生物体 MEP 途径抑制剂的发现。

• 批准号: 8058854
• 负责人: Bart Lee Staker
• 金额: $ 10万
• 依托单位: EMERALD BIOSTRUCTURES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058854
• 关键词: Binding; Chemicals; Clinic; Clinical; Combined Modality Therapy; Communicable Diseases; Complex; Data; Development; Disease; Drug Design; Drug resistance; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Goals; Grant; Human; In Vitro; Infection; Infectious Agent; Lead; Malaria; Methods; NMR Spectroscopy; Organism; Pathway interactions; Phase; Risk; Screening procedure; Structure; Tuberculosis; X-Ray Crystallography; base; combat; cytotoxicity; design; in vivo; inhibitor/antagonist; isoprenoid; microbial; novel; pathogen; potency testing; resistant strain; small molecule; success

DESCRIPTION (provided by applicant): We will apply nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to study enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway, which is essential in multiple pathogens and absent in humans. Identification and biophysical characterization of fragments which bind to MEP targets will generate data for the rational design of small molecule leads for MEP enzymatic inhibition. Through iterative synthesis and structure determination, we will develop these leads into novel compounds capable of binding MEP enzymes from a variety of infectious disease organisms. Success in this endeavor would lead to a Phase II proposal for focused synthesis and in vitro/in vivo potency testing to prove efficacy and advance these compounds closer to the clinic. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage PUBLIC HEALTH RELEVANCE: This project proposes to utilize biophysical methods to discover lead compounds that bind to enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage.

描述（由申请人提供）：我们将应用核磁共振（NMR）光谱学和X射线晶体学来研究来自甲基异戊二烯（MEP）生物合成途径的酶，该途径在多种病原体中是必需的，在人类中是不存在的。结合MEP靶标的片段的鉴定和生物物理表征将产生用于MEP酶抑制的小分子先导物的合理设计的数据。通过迭代合成和结构测定，我们将开发这些线索成为新的化合物，能够结合MEP酶从各种传染病生物体。这一奋进的成功将导致II期提案，用于集中合成和体外/体内效力测试，以证明疗效并使这些化合物更接近临床。该项目的最终目标是为那些感染疟疾，结核病和其他微生物感染的耐药菌株的人开发新的治疗方法，因为目前没有MEP途径抑制剂组合疗法被批准用于临床使用 公共卫生关系：该项目提出利用生物物理方法来发现与甲基异戊二烯（MEP）生物合成途径中的酶结合的先导化合物。该项目的最终目标是为感染疟疾，结核病和其他微生物感染的耐药菌株的患者开发新的治疗方法，因为目前还没有MEP途径抑制剂组合疗法被批准用于临床。

项目成果

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei.

• DOI: 10.1007/s10969-011-9102-6
• 发表时间: 2011-07
• 期刊: Journal of structural and functional genomics
• 作者: Begley, Darren W;Hartley, Robert C;Davies, Douglas R;Edwards, Thomas E;Leonard, Jess T;Abendroth, Jan;Burris, Courtney A;Bhandari, Janhavi;Myler, Peter J;Staker, Bart L;Stewart, Lance J
• 通讯作者: Stewart, Lance J

Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei.

胞苷衍生物作为鼻疽伯克氏菌的 IspF 抑制剂。

• DOI: 10.1016/j.bmcl.2013.09.101
• 发表时间: 2013
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Zhang,Zheng;Jakkaraju,Sriram;Blain,Joy;Gogol,Kenneth;Zhao,Lei;Hartley,RobertC;Karlsson,CourtneyA;Staker,BartL;Edwards,ThomasE;Stewart,LanceJ;Myler,PeterJ;Clare,Michael;Begley,DarrenW;Horn,JamesR;Hagen,TimothyJ
• 通讯作者: Hagen,TimothyJ