Redox Balance & Drug Development in Schistosoma mansoni

氧化还原平衡

基本信息

批准号：
7587323
负责人：
DAVID LEE WILLIAMS
金额：
$ 26.57万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587323
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（由申请人提供）：血吸虫病是一种重要的热带寄生虫疾病。尽管正在使用一种有效的抗速溶药物，但据估计，有2亿人被感染，2000万人患有严重的疾病症状，每年有28万人死于血吸虫病。此外，使用药物的传播率有所改变，并且有证据表明耐药寄生虫的发展。由于目前尚无合适的替代疗法，因此迫切需要开发新型的反chistosomal剂。在此应用中，我们建议将重点放在寄生虫生化氧化还原机制上，以作为反毒体药物开发的新靶标。其确定性和中间宿主中的血吸虫必须能够在免疫和自我产生的活性氧化合物存在下生存，并为许多关键的酶促途径提供二硫化物还原等效物。在大多数生物体中，有两个可提供氧化防御和减少功率的平行系统，一个基于谷胱甘肽，另一个基于硫氧还蛋白。我们最近的结果表明，曼森血吸虫与哺乳动物宿主具有根本不同的氧化还原机制。蠕虫完全不存在两个关键的氧化还原酶，谷胱甘肽还原酶和硫氧还蛋白还原酶。取而代之的是，这些活性在单个蛋白硫氧还蛋白 - 谷胱甘肽还原酶（TGR）中一起发现。我们已经表明，TGR是一种必不可少的寄生虫蛋白，抑制TGR会导致寄生虫死亡。在研究建议中，我们将：（1）基于铅化合物合成潜在的TGR抑制剂，我们已经确定并确定其对寄生虫和寄生虫和宿主酶的相对抑制活性及其对培养的蠕虫和哺乳动物细胞的毒性，（2）为TGR的催化机制而开发了TRED，该假设将进一步发展，以进一步发展TGR的抑制作用，（3）适用于TGR的抑制作用（3）。它的3D药物改进结构。由于血块中的二硫键氧化还原平衡集中在单个关键的氧化还原酶上，并且与我们提出的利用该寄生虫途径的宿主机制有根本不同，这是用于理性药物设计的有希望的目标。