Novel targets and drugs for the control of platyhelminth infections

控制扁形虫感染的新靶点和药物

• 批准号: 7840690
• 负责人: Marcos Gustavo Salinas
• 金额: $ 4.32万
• 依托单位: FUNDAQUIM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840690
• 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; 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

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）：由扁虫（扁形虫）引起的寄生虫感染是被忽视的疾病，也是许多发展中国家残疾、死亡和重大经济损失的主要原因。扁形虫感染的大规模治疗依赖于单一药物：吡喹酮，而耐药性的出现是迫在眉睫的威胁。新药的鉴定，特别是如果它们通过不同的机制针对寄生虫，是最贫困地区和国家公共卫生的一个重要目标。我们已经证明，扁形动物寄生虫的氧化还原稳态和抗氧化防御完全依赖于单一酶，即硫氧还蛋白谷胱甘肽还原酶（TGR）。这种生化情况与宿主的生化情况不同，后者存在相关但不同的途径。最近的血吸虫病研究证实了 TGR 是一种新型合理的药物靶点，并表明恶二唑 N-氧化物作为治疗血吸虫病的新药物具有广阔的前景。在这个项目中，我们将鉴定出有效且特异性的扁形动物 TGR 抑制剂，选择性地干扰扁虫氧化还原稳态。在比较酶抑制测定中，我们将使用：i) 一组来自绦虫和吸虫（扁形虫寄生虫的两大类）的重组 TGR，以及人重组硫氧还蛋白还原酶和 TGR，以及 ii) 一组恶二唑 N-氧化物和金配位化合物已被确定为细粒棘球绦虫 TGR 的抑制剂。我们将评估最佳抑制剂的效果（i）在体外使用培养的寄生虫； (ii) 啮齿动物模型体内。对于最佳抑制剂，将表征抑制机制。将根据获得的结果以及计算机对接和神经网络预测进行系列扩展。此外，我们将进一步研究扁形动物TGR的催化和调控作用。我们将研究：i) 谷胱甘肽还原机制，ii) 扁虫 TGR 的去谷胱甘肽活性，以及​​ iii) TGR 中调节性半胱氨酸的作用。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高度相关。 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相关，并对贫穷国家构成沉重负担。这些感染的大规模治疗依赖于单一药物，人们有理由担心耐药寄生虫的出现以及对新药的迫切需求。我们提出了一种通过识别选择性干扰寄生虫氧化还原稳态的药物来治疗扁虫感染的直接方法。