Development of a novel nematode/Wolbachia target

新型线虫/沃尔巴克氏体靶标的开发

• 批准号: 7051638
• 负责人: CLOTILDE CARLOW
• 金额: $ 41.38万
• 依托单位: NEW ENGLAND BIOLABS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051638
• 关键词: Caenorhabditis elegans; Filarioidae; Nematoda; Rickettsiales; Wuchereria; anthelmintics; drug design /synthesis /production; drug discovery /isolation; drug receptors; drug screening /evaluation; enzyme inhibitors; helminthiasis; high throughput technology; molecular cloning; nucleic acid sequence; phosphoglycerate mutase; protein quantitation /detection; recombinant proteins; symbiosis

DESCRIPTION (provided by applicant): Parasitic nematodes are responsible for a number of severe diseases in humans, animals and plants. Approximately $600 million is spent each year on drugs to treat nematode infections in animals. These drugs are not completely effective so the discovery of new therapies and drug targets is of paramount importance. Recently we employed a novel bioinformatics approach to identify valid drug targets in nematodes that are absent from mammals. A particularly promising enzyme target has been discovered and validated which merits further development. Phase I of this project led to the successful development of a target-based screening system and assays to measure enzyme activity and inhibition. Pilot screening of various libraries has commenced and hits have been obtained which are being characterized further. With Phase II funding, we will perform more extensive screening with the goal of identifying potent inhibitors of enzyme activity. The hits will be evaluated further for broad-spectrum enzyme inhibitory activity by measuring their effects on the target isolated from other nematodes. To determine target specificity, hits will be tested in other assays involving distantly related enzymes. Non-specific cytotoxicity will be determined using mammalian cell lines. The most promising inhibitors will be evaluated for nematocidal and anti-bacterial activity in various in vitro and in vivo systems. Active compounds may also be tested for their effects on other organisms that possess the target. This will provide the basis for discovering a new class of drugs that may be used in veterinary and human medicine.

描述（由申请人提供）：寄生线虫导致人类、动物和植物的许多严重疾病。每年大约花费 6 亿美元用于治疗动物线虫感染的药物。这些药物并不完全有效，因此发现新疗法和药物靶点至关重要。最近，我们采用了一种新颖的生物信息学方法来识别哺乳动物中不存在的线虫中的有效药物靶点。已经发现并验证了一种特别有前途的酶靶点，值得进一步开发。该项目的第一阶段成功开发了基于靶标的筛选系统和测量酶活性和抑制的测定方法。对各个文库的试点筛选已经开始，并且已经获得了命中，这些命中正在进一步表征。借助第二阶段的资金，我们将进行更广泛的筛选，目的是识别酶活性的有效抑制剂。通过测量它们对从其他线虫中分离出的靶标的影响，将进一步评估这些命中物的广谱酶抑制活性。为了确定目标特异性，将在涉及远缘相关酶的其他测定中测试命中。非特异性细胞毒性将使用哺乳动物细胞系测定。最有前途的抑制剂将在各种体外和体内系统中评估其杀线虫和抗菌活性。还可以测试活性化合物对具有目标的其他生物体的影响。这将为发现可用于兽医和人类医学的新型药物奠定基础。