Defining target specificity of oxadiazole 2-oxides in Ancylostoma ceylanicum

描述（由申请人提供）： 摘要 PI：VERMEIRE，JON J. 项目：1 K22 AI 089969 -01标题：确定锡兰钩虫中恶二唑2-氧化物的靶标特异性登录号：3233568 ================== 注意事项：本摘要摘自应用程序，未经SRA验证。当应用程序扫描过程出现问题时，提取的文本可能不正确或不完整。 ================== J.在发展中国家，钩虫仍然是一个主要的健康负担，目前有数亿人受到这些吸血寄生虫的折磨。未来的努力，以大大减少钩虫病可能需要加入传统的控制方法与替代战略，如疫苗和新的治疗方法。制定这样的战略需要确定寄生虫生存所必需的目标。在这方面，钩虫酶参与血粉代谢是有吸引力的药物和疫苗的目标。除了提供必需的营养素外，吸血还使钩虫暴露于潜在有毒的含铁化合物，其介导自由基和氧化产物的产生。因此，它是非常有可能的成年钩虫，积极地在宿主的血液喂养，已经发展出一种有效的机制，解毒的活性氧物质，通过红细胞的溶血和蛋白酶介导的消化血红蛋白。肠道线虫的抗氧化系统是蠕虫生物学中一个非常重要但尚未充分研究的领域。因此，该提案的一个重要方面包括钩虫抗氧化途径的表征，以更好地了解它们在寄生虫生物学和宿主发病机制中的作用。提案中概述的研究的另一个重点是确定恶二唑2-氧化物在人类钩虫Ancylostoma ceylanicum中的靶点。初步数据显示，这些一氧化氮供体化合物对A.锡兰最近的工作已经确定恶二唑作为先导化合物靶向吸虫多功能氧化还原蛋白，硫氧还蛋白谷胱甘肽还原酶（TGR），并建议其疗效作为新的药物蠕虫。钩虫不表达这种基因产物，而是依赖于硫氧还蛋白和谷胱甘肽还原酶活性的单独酶。因此，恶二唑杀死钩虫的机制仍然未知。本实验的目的是：1）系统地鉴定和表征A. 2）明确了恶二唑类化合物对A. ceylanicum氧化还原途径成员，和3）废除成人A.使用中和抗体和恶二唑化合物测定锡兰藻体内氧化还原活性。实验设计包括允许PI在对未来成功至关重要的领域发展技术技能的方法。该提案具体概述了K22支持将如何通过为科学发展和专业成长提供重要机会来增强和建立PI以前的研究经验和博士后培训。这个K22奖的资金将最大限度地发挥PI的潜力，以建立自己作为一个独立的研究者，以作出有意义的贡献，分子蠕虫学领域。J. Vermeire

DESCRIPTION (provided by applicant): Abstract PI: VERMEIRE, JON J. Project: 1K22AI089969-01 Title: Defining target specificity of oxadiazole 2-oxides in Ancylostoma ceylanicum Accession Number: 3233568 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== J. Vermeire - Project Summary/Abstract Hookworms remain a major health burden in the developing world, with hundreds of millions currently afflicted by these bloodfeeding parasites. Future efforts to substantially reduce hookworm disease will likely require the joining of conventional control methods with alternative strategies such as vaccines and novel therapeutics. Development of such strategies requires identification of targets essential for parasite survival. In this regard hookworm enzymes involved in bloodmeal metabolism are attractive drug and vaccine targets. In addition to providing essential nutrients, bloodfeeding also exposes hookworms to potentially toxic iron-containing compounds, which mediate the generation of free radicals and oxidative products. Thus, it is highly likely that the adult hookworm, which feeds aggressively on host blood, has evolved an efficient mechanism for detoxifying the reactive oxygen species that are generated through hemolysis of red blood cells and protease mediated digestion of hemoglobin. Antioxidant systems of bloodfeeding, intestinal nematodes represent an extremely important yet understudied area of helminth biology. Therefore, one important aspect of the proposal includes characterization of hookworm antioxidant pathways in order to better understand their role in parasite biology and host pathogenesis. The other focus of the research outlined in the proposal is to define the target(s) of oxadiazole 2-oxides in the human hookworm Ancylostoma ceylanicum. Preliminary data reveal that these nitric oxide-donating compounds are highly toxic to the adult stages of A. ceylanicum. Recent work has identified oxadiazoles as lead compounds targeting the trematode multifunctional redox protein, thioredoxin glutathione reductase (TGR), and suggest their efficacy as new drugs for helminths. Hookworms do not express this gene product, instead relying on separate enzymes for thioredoxin and glutathione reductase activities. Therefore, the mechanism by which oxadiazoles kill hookworms remains unknown. The proposed experiments are designed to 1) systematically identify and characterize the thiol redox pathways in A. ceylanicum, 2) define target specificity and inhibitory action of oxadiazole compounds on A. ceylanicum redox pathway members, and 3) abrogate adult A. ceylanicum redox activities in vivo using neutralizing antibodies and oxadiazole compounds. The experimental design includes methodologies that will allow the PI to develop technical skill in areas critical to future success. The proposal specifically outlines how K22 support will augment and build upon the PI's previous research experience and postdoctoral training by providing essential opportunities for scientific development and professional growth. Funding of this K22 award will maximize the potential of the PI to establish himself as an independent investigator in order to make a meaningful contribution to the field of molecular helminthology. J. Vermeire -