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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：
8532682
负责人：
Eric Oldfield
金额：
$ 33.53万
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 2014-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532682
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 Targeting 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）：本研究的目的是使用EPR、ENDOR、NMR、X射线晶体学、合成和计算方法的组合来研究感兴趣的类异戊二烯生物合成酶的结构、功能和抑制作用，作为治疗主要是热带疾病的药物靶点。在目的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。我们推测，其作用机制涉及不寻常的金属杂环和类似的金属杂环形式与新的炔抑制剂。GcpE是开发新型抗感染药物的一个很好的靶点，因为它是病原体生存所必需的，在人类中没有发现，我们现在已经确定了新的抑制剂。在目标2中，我们将对途径中的以下酶（来自恶性疟原虫）LytB进行类似的一系列研究，并且我们假设，由于它们的作用机制相似，LytB抑制剂也将抑制GcpE，从而在细胞中产生协同活性。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药。类胡萝卜素的作用是去除活性氧（ROS，从血红蛋白catalysts），我们假设类胡萝卜素（和醌）生物合成抑制剂将协同与目前的抗疟药（增强ROS的形成），减少耐药性。最后的目标涉及调查其他三个高价值的目标：在锥虫寄生虫，法呢基二磷酸合酶和己糖激酶，在细菌，十一异戊二烯基二磷酸合酶。所有这些都是生存所必需的，我们已经确定了亚微摩尔的铅。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。重点将是开发针对疟疾寄生虫中三个独特靶标的抑制剂，以及使用新型药物对抗昏睡病。