Prenyl Synthase Inhibitors: Novel Anti-Infective Agents

异戊二烯合酶抑制剂：新型抗感染剂

• 批准号: 7984564
• 负责人: Eric Oldfield
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984564
• 关键词: African Trypanosomiasis; Alkanesulfonates; Alkynes; Amino Acids; Anabolism; Anti-Infective Agents; Antimalarials; Bacteria; Binding; Biological Assay; Carotenoids; Catabolism; Catalysis; Cells; Chemicals; Collaborations; Combined Modality Therapy; Communicable Diseases; Computing Methodologies; Confocal Microscopy; Crystallography; Development; Diphosphates; Drug Delivery Systems; Drug resistance; Electron Nuclear Double Resonance; Enzyme Inhibition; Enzymes; Epoxy Compounds; Erythrocytes; Geranyltranstransferase; Grant; Growth Inhibitors; Hemoglobin; Human; In Situ; Investigation; Lead; Malaria; Methods; Monobactams; Organometallic Chemistry; Oxidoreductase; Parasites; Pathway interactions; Pharmaceutical Preparations; Physical condensation; Plasmodium; Plasmodium falciparum; Proteins; Protozoa; Quantitative Structure-Activity Relationship; Quinones; Reaction; Reactive Oxygen Species; Reporting; Research; Roentgen Rays; Route; Series; Site-Directed Mutagenesis; Staging; Staphylococcus aureus; Structure; Testing; Tropical Disease; Work; analog; base; bisphosphonate; carboxylate; chemical synthesis; computational chemistry; design; enzyme biosynthesis; enzyme mechanism; fosmidomycin; geranylgeranyl diphosphate; hemozoin; hexokinase; high throughput screening; in vivo; inhibitor/antagonist; inorganic phosphate; insight; interest; isopentenyl pyrophosphate; isoprenoid; killings; methicillin resistant Staphylococcus aureus; mevalonate; novel; novel strategies; pathogen; phytoene; prenyl; public health relevance; quantum; undecaprenyl pyrophosphate synthetase

DESCRIPTION (provided by applicant): The objective of this research is to use a combination of EPR, ENDOR, NMR, X-ray crystallographic, synthetic and computational methods to investigate the structure, function, and inhibition of isoprenoid biosynthesis enzymes of interest as drug targets for treating, primarily, tropical diseases. In Aim 1, we will investigate GcpE, an enzyme involved in isoprenoid biosynthesis in malaria parasites. We hypothesize that its mechanism of action involves unusual metallacycles and that similar metallacycles form with novel alkyne inhibitors. GcpE is an excellent target for the development of novel anti-infectives since it is essential for pathogen survival, is not found in humans, and we have now identified novel inhibitors. In Aim 2 we will carry out a similar series of investigations of the following enzyme (from P. falciparum) in the pathway, LytB, and we hypothesize that because of similarities in their mechanism of action, LytB inhibitors will also inhibit GcpE leading, in cells, to synergistic activity. The third Aim is to develop novel anti-malarials that function by blocking carotenoid and quinone biosynthesis. Carotenoids act to remove reactive oxygen species (ROS, from hemoglobin catabolism) and we hypothesize that carotenoid (and quinone) biosynthesis inhibitors will synergize with current anti-malarials (that enhance ROS formation), reducing drug resistance. The final Aim involves investigation of three other high-value targets: in trypanosomatid parasites, farnesyl diphosphate synthase and hexokinase, in bacteria, undecaprenyl diphosphate synthase. All are essential for survival and sub-micromolar leads have already been identified by us. If successful, the work will provide many new insights into enzyme mechanisms, as well as new drug leads for many global infectious diseases. PUBLIC HEALTH RELEVANCE: This project is aimed at developing new leads for treating infectious diseases, primarily malaria. Focus will be on developing inhibitors for three unique targets in malaria parasites, and on the use of novel drugs against sleeping sickness.

描述(申请人提供)：这项研究的目的是使用EPR、Endor、核磁共振、X射线结晶学、合成和计算方法相结合的方法来研究感兴趣的异戊二烯生物合成酶的结构、功能和抑制，作为治疗主要是热带疾病的药物靶标。在目标1中，我们将研究GcpE，一种参与疟疾寄生虫类异戊二烯生物合成的酶。我们假设它的作用机制涉及不寻常的金属环，类似的金属环与新型的炔类抑制剂形成。GcpE是开发新型抗感染药物的极佳靶点，因为它对病原体的生存是必不可少的，在人类中没有发现，而且我们现在已经发现了新的抑制剂。在目标2中，我们将对途径LytB中的以下酶(来自恶性疟原虫)进行类似的一系列研究，并假设由于其作用机制相似，LytB抑制剂也将抑制GcpE在细胞中的协同活性。第三个目标是开发新型抗疟疾药物，通过阻断类胡萝卜素和苯醌的生物合成发挥作用。类胡萝卜素的作用是清除血红蛋白分解代谢中的活性氧物种(ROS)，我们假设类胡萝卜素(和苯二酚)生物合成抑制剂将与当前的抗疟疾药物(增强ROS形成)协同作用，降低耐药性。最终目标包括对其他三个高价值靶标的研究：在锥虫寄生虫中，法尼基二磷酸合成酶和己糖激酶，在细菌中，十一碳烯基二磷酸合成酶。所有这些都是生存所必需的，我们已经发现了亚微摩尔铅。如果成功，这项工作将为酶的机制提供许多新的见解，并为许多全球传染病提供新的药物线索。 公共卫生相关性：该项目旨在开发治疗传染病(主要是疟疾)的新线索。重点将放在为疟疾寄生虫的三个独特靶点开发抑制剂，以及使用治疗昏睡病的新药。