Novel targets and drugs for the control of platyhelminth infections

控制扁形虫感染的新靶点和药物

基本信息

批准号：
8250254
负责人：
Marcos Gustavo Salinas
金额：
$ 4.28万
依托单位：
FUNDAQUIM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250254
关键词：
Abbreviations Acids Active Sites Address Antioxidants Back Behavior Biochemical Biological Assay Biological Neural Networks Catalysis Cestoda Computer Simulation Country Cysteine DNA Insertion Elements Data Developing Countries Disease Docking Drug Controls Drug Delivery Systems Drug resistance Eagles Echinococcus granulosus Economics Enzymes Exhibits Generations Glutathione Glutathione Disulfide Glutathione Reductase Goals Gold Grant Homeostasis Human Hybrids In Vitro Infection Isopropyl Thiogalactoside Libraries Mono-S Morbidity - disease rate Oxadiazoles Oxidation-Reduction Oxides Parasites Parasitic infection Pathway interactions Pharmaceutical Preparations Platyhelminths Praziquantel Public Health Quantitative Structure-Activity Relationship Recombinants Reduced Glutathione Regulation Research Rodent Rodent Model Role Schistosomiasis Selenocysteine Series Structure Sulfhydryl Compounds Thioredoxin Trematoda Tropical Disease United States National Institutes of Health Uruguay Work base comparative design disability global health glutaredoxin high throughput screening in vivo inhibitor/antagonist insight mortality neglect novel public health relevance thioredoxin glutathione reductase thioredoxin reductase

项目摘要

DESCRIPTION (provided by applicant): Parasitic infections caused by flatworms (platyhelminths) are neglected diseases and a major cause of disability, mortality and significant economic losses in many developing countries. Large-scale treatment of flatworm infections relies on a single drug available: praziquantel, and the emergence of drug resistance is an impending menace. The identification of novel drugs, in particular if they target the parasite by a different mechanism, is an important goal in public health in the poorest regions and countries. We have demonstrated that the redox homeostasis and antioxidant defenses of platyhelminth parasites are fully dependent on a single enzyme, thioredoxin glutathione reductase (TGR). This biochemical scenario differs from that of the host where there are related but distinct pathways. Recent studies in schistosomiasis validated TGR as a novel rational drug target, and have shown that oxadiazole N-oxides offer great promise as new drug leads for schistosomiasis. In this project, we will identify effective and specific inhibitors of platyhelminth TGRs, selectively disturbing flatworm redox homeostasis. In comparative enzymatic inhibition assays we will use: i) a panel of recombinant TGRs from tapeworms and flukes (the two major groups of platyhelminth parasites) as well as human recombinant thioredoxin reductases and TGR, and ii) a panel of oxadiazole N-oxides and gold coordination compounds already identified as inhibitors of Echinococcus granulosus TGR. We will assess the effect of best inhibitors (i) in vitro using cultured parasites; and (ii) in vivo in rodent models. For best inhibitors the mechanism of inhibition will be characterized. Series expansion will be carried out based on the results obtained and in silico docking and neural network predictions. In addition, we will further investigate catalysis and regulation of platyhelminth TGRs. We will study: i) the mechanism of glutathione reduction, ii) deglutathionylation activity of flatworm TGRs, and iii) the role of regulatory cysteine(s) in TGR. These biochemical studies will assist in drug optimization and design. The project addresses a significant global health problem, with high relevance to Uruguay and other countries. PUBLIC HEALTH RELEVANCE: Neglected tropical diseases caused by flatworm infections are associated with high morbidity and mortality and constitute a heavy burden to poor countries. Large-scale treatment of these infections relies on a single drug and there is justified concern regarding the emergence of drug-resistant parasites, and a pressing need for new drugs. We propose a straightforward approach to treat flatworm infections by identifying drugs selectively interfering with the redox homeostasis of the parasites.

描述（由申请人提供）：许多发展中国家的残疾，死亡率和重大经济损失的疾病是由扁虫引起的寄生虫感染（Platyhelminths）。扁虫感染的大规模治疗依赖于一种可用的药物：praziquantel，耐药性的出现即将来临。新型药物的识别，特别是如果它们通过不同的机制瞄准寄生虫，则是最贫穷地区和国家公共卫生的重要目标。我们已经证明，铂赫敏寄生虫的氧化还原稳态和抗氧化剂防御完全取决于单一酶硫氧还蛋白谷胱甘肽还原酶（TGR）。这种生化场景与相关但途径不同的宿主的情况不同。血吸虫病的最新研究验证了TGR作为一种新型的合理药物靶标，并表明，随着新药的新药物铅的血吸虫病，Oxadiazole N-氧化物具有很大的希望。在这个项目中，我们将确定铂螺旋体TGRS的有效且特定的抑制剂，有选择地干扰扁虫氧化还原稳态。在比较酶促抑制测定中，我们将使用：i）来自tape虫和氟化物（两个主要的Platyhelminth寄生虫组）的重组TGR，以及人类重组硫氧还蛋白还原酶和TGR，以及II）黄金配位化合物已经被鉴定为echinococcus颗粒TGR的抑制剂。我们将使用培养的寄生虫在体外评估最佳抑制剂（i）的作用；（ii）啮齿动物模型中的体内。对于最佳抑制剂，将表征抑制的机制。系列扩展将根据获得的结果以及在硅网站和神经网络预测中进行。此外，我们将进一步研究PlatyHelminth TGRS的催化和调节。我们将研究：i）谷胱甘肽还原的机理，ii）扁虫TGRS的脱氟二硫代化活性，iii）调节性半胱氨酸在TGR中的作用。这些生化研究将有助于药物优化和设计。该项目解决了一个重大的全球健康问题，与乌拉圭和其他国家相关。公共卫生相关性：由扁虫感染引起的被忽视的热带疾病与高发病率和死亡率有关，并构成了贫困国家的沉重负担。对这些感染的大规模治疗依赖于一种药物，并且对抗药性寄生虫的出现以及对新药的紧迫需求有正当的关注。我们提出了一种直接的方法来通过选择性干扰寄生虫的氧化还原稳态来治疗扁虫感染。