Prenyl Synthase Inhibitors: Novel Anti-Infective Agents

异戊二烯合酶抑制剂：新型抗感染剂

基本信息

批准号：
8128720
负责人：
Eric Oldfield
金额：
$ 34.76万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
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/8128720
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 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 novel novel strategies pathogen phytoene prenyl public health relevance quantum undecaprenyl pyrophosphate synthetase

项目摘要

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（由申请人提供）：本研究的目的是结合使用 EPR、ENDOR、NMR、X 射线晶体学、合成和计算方法来研究作为药物的类异戊二烯生物合成酶的结构、功能和抑制作用主要治疗热带疾病的目标。在目标 1 中，我们将研究 GcpE，一种参与疟原虫类异戊二烯生物合成的酶。我们假设其作用机制涉及不寻常的金属环，并且类似的金属环与新型炔烃抑制剂形成。 GcpE 是开发新型抗感染药物的绝佳靶点，因为它对于病原体的生存至关重要，但在人类中并未发现，而且我们现在已经鉴定出新型抑制剂。在目标 2 中，我们将对途径 LytB 中的以下酶（来自恶性疟原虫）进行一系列类似的研究，并且我们假设，由于其作用机制相似，LytB 抑制剂也会抑制 GcpE 导致，细胞，发挥协同活性。第三个目标是开发通过阻断类胡萝卜素和醌生物合成发挥作用的新型抗疟疾药物。类胡萝卜素的作用是去除活性氧（ROS，来自血红蛋白分解代谢），我们假设类胡萝卜素（和醌）生物合成抑制剂将与当前的抗疟疾药物（增强 ROS 形成）产生协同作用，从而降低耐药性。最终目标涉及对其他三个高价值目标的研究：锥虫寄生虫中的法尼基二磷酸合酶和己糖激酶，细菌中的十一异戊二烯基二磷酸合酶。所有这些对于生存都是至关重要的，我们已经确定了亚微摩尔引线。如果成功，这项工作将为酶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先导物。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。重点将是开发针对疟原虫三个独特靶点的抑制剂，以及使用新药物来治疗昏睡病。