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Redox Balance & Drug Development in Schistosoma mansoni

氧化还原平衡

基本信息

批准号：
8044689
负责人：
DAVID LEE WILLIAMS
金额：
$ 26.04万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044689
关键词：
Affect Alternative Therapies Antischistosomal Agents Apoptosis Biochemical Catalysis Cessation of life Chagas Disease Collaborations Crystallization DNA biosynthesis Development Disease Disulfides Drug Design Drug Metabolic Detoxication Drug resistance Drug usage Enzymes Equilibrium Gene Expression Glutathione Glutathione Disulfide Glutathione Reductase Goals Human Hydrogen Peroxide Immune Immune response Individual Kinetics Knowledge Lead Malaria Malignant Neoplasms Mammalian Cell Mannich Bases Michigan NADP Naphthoquinones Oregon Organism Oxidation-Reduction Oxidoreductase Parasites Pathway interactions Pharmaceutical Preparations Praziquantel Process Production Protein Inhibition Protein S Proteins Relative (related person)Research Proposals Schistosoma Schistosoma mansoni Schistosomiasis Snails Structure Superoxides Symptoms System Thioredoxin Toxic effect Universities base chemotherapy design disorder control drug development human disease inhibitor/antagonist novel oxygen compounds programs pyridine nucleotide reactive oxygen intermediate thioredoxin glutathione reductase thioredoxin reductase three dimensional structure transmission process

项目摘要

DESCRIPTION (provided by applicant): Schistosomiasis is an important tropical parasitic human disease. Although an effective anti-schistosome drug is in use, it is estimated that 200 million people remain infected, 20 million individuals suffer severe disease symptoms, and 280,000 people die annually from schistosomiasis. Furthermore, transmission rates have changed a little with the use of the drug and there is evidence for the development of drug resistant parasites. Because there is currently no suitable alternative therapy available there is an urgent need for the development of novel antischistosomal agents. In this application we propose to focus on parasite biochemical redox mechanisms as novel targets for antischistosomal drug development. Schistosomes in their definitive and intermediate hosts must be able to survive in the presence of both immune and self generated reactive oxygen compounds and provide disulfide reducing equivalents for a number of critical enzymatic pathways. Two parallel systems to provide oxidative defense and reducing power occur in most organisms, one based on glutathione and the other based on thioredoxin. Our recent results indicate that Schistosoma mansoni has fundamentally different redox mechanisms from their mammalian host. Entirely absent from worms are two key redox enzymes, glutathione reductase and thioredoxin reductase. Instead, these activities are found together in a single protein thioredoxin-glutathione reductase (TGR). We have shown that TGR is an essential parasite protein and that inhibition of the TGR leads to parasite death. In the research proposal we will: (1) synthesize potential TGR inhibitors based on lead compounds we have already identified and determine their relative inhibitory activity against parasite and host enzymes and their toxicity to cultured worms and mammalian cells, (2) develop an hypothesis for the catalytic mechanism of TGR, which will further the development of TGR inhibitors and, (3) define conditions suitable for the crystallization of TGR and determine its 3D structure for drug refinement. Because disulfide redox balance in schistosomes is centered on a single key redox enzyme and is fundamentally different from host mechanisms we propose in exploit this parasite pathway as a promising target for rational drug design.

描述（申请人提供）：血吸虫病是一种重要的热带人类寄生虫病。虽然使用了一种有效的抗血吸虫药物，但估计仍有2亿人感染，2 000万人患有严重的疾病症状，每年有28万人死于血吸虫病。此外，由于使用该药物，传播率略有变化，有证据表明出现了耐药寄生虫。由于目前还没有合适的替代疗法，因此迫切需要开发新的抗血吸虫药。在这一应用中，我们建议将寄生虫的生化氧化还原机制作为抗血吸虫药物开发的新靶点。血吸虫在其最终宿主和中间宿主中必须能够在免疫和自身产生的活性氧化合物存在下存活，并为许多关键的酶促途径提供二硫还原等量物。在大多数生物体中存在两个平行的系统来提供氧化防御和还原能力，一个基于谷胱甘肽，另一个基于硫氧还蛋白。我们最近的研究结果表明，曼氏血吸虫的氧化还原机制与其哺乳动物宿主完全不同。蠕虫完全没有两种关键的氧化还原酶，谷胱甘肽还原酶和硫氧还蛋白还原酶。相反，这些活性是在单一蛋白质硫氧还蛋白-谷胱甘肽还原酶（TGR）中发现的。我们已经证明TGR是一种必需的寄生虫蛋白，抑制TGR会导致寄生虫死亡。在研究计划中，我们将：(1)基于我们已经鉴定的先导化合物合成潜在的TGR抑制剂，并确定其对寄生虫和宿主酶的相对抑制活性以及对培养的蠕虫和哺乳动物细胞的毒性；(2)对TGR的催化机制进行假设，这将进一步发展TGR抑制剂；(3)确定TGR结晶的合适条件并确定其3D结构以用于药物精制。由于血吸虫的二硫氧化还原平衡以一个关键的氧化还原酶为中心，与宿主机制有着根本的不同，因此我们提出利用这一寄生虫途径作为合理药物设计的有希望的靶点。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Moonlighting by different stressors: crystal structure of the chaperone species of a 2-Cys peroxiredoxin.

DOI：
10.1016/j.str.2012.01.004
发表时间：
2012-03-07
期刊：
STRUCTURE
影响因子：
5.7
作者：
Saccoccia, Fulvio;Di Micco, Patrizio;Boumis, Giovanna;Brunori, Maurizio;Koutris, Ilias;Miele, Adriana E.;Morea, Veronica;Sriratana, Palita;Williams, David L.;Bellelli, Andrea;Angelucci, Francesco
通讯作者：
Angelucci, Francesco

On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases.

DOI：
10.1016/j.jinorgbio.2011.11.005
发表时间：
2012-03
期刊：
JOURNAL OF INORGANIC BIOCHEMISTRY
影响因子：
3.9
作者：
Saccoccia, Fulvio;Angelucci, Francesco;Boumis, Giovanna;Brunori, Maurizio;Miele, Adriana E.;Williams, David L.;Bellelli, Andrea
通讯作者：
Bellelli, Andrea

New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni.

DOI：
10.1016/j.ejmech.2014.07.007
发表时间：
2014-09-12
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Guglielmo S;Cortese D;Vottero F;Rolando B;Kommer VP;Williams DL;Fruttero R;Gasco A
通讯作者：
Gasco A

Investigations of the catalytic mechanism of thioredoxin glutathione reductase from Schistosoma mansoni.