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：1K22AI089969-01标题：确定头孢钩虫中恶二唑2-氧化物的靶标特异性登录号：3233568 = 注意：此摘要摘自应用程序，未经SRA校对。如果应用程序扫描过程有问题，提取的文本可能不正确或不完整。 = J.Vermeire-项目摘要/摘要钩虫仍然是发展中国家的主要健康负担，目前有数亿人受到这些吸血寄生虫的困扰。未来大幅减少钩虫疾病的努力可能需要将传统控制方法与疫苗和新疗法等替代战略结合起来。这种策略的发展需要确定对寄生虫生存至关重要的目标。在这方面，参与血粉代谢的钩虫酶是有吸引力的药物和疫苗靶标。除了提供必要的营养外，吸血还会使钩虫暴露于潜在的有毒含铁化合物中，这些化合物会调节自由基和氧化产物的生成。因此，这种以宿主血液为食的成虫很可能已经进化出一种有效的机制来解毒通过红细胞溶血和蛋白酶介导的血红蛋白消化而产生的活性氧物种。肠道线虫作为血液中的抗氧化系统，是蠕虫生物学中一个极其重要但研究不足的领域。因此，该提案的一个重要方面包括表征钩虫的抗氧化途径，以便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。提案中概述的另一个研究重点是确定恶二唑2-氧化物在人钩虫体内的靶标(S)。初步数据显示，这些一氧化氮供体化合物对天牛成虫有很强的毒性。最近的工作已经确定恶二唑是针对吸虫多功能氧化还原蛋白硫氧还蛋白谷胱甘肽还原酶(TGR)的先导化合物，并表明它们作为治疗蠕虫的新药的有效性。钩虫不表达这种基因产物，而是依赖单独的酶来获得硫氧还蛋白和谷胱甘肽还原酶的活性。因此，恶二唑杀死钩虫的机制尚不清楚。这些实验的目的是：1)系统地鉴定和表征头孢曲霉中的硫醇氧化还原途径；2)确定恶二唑化合物对头孢曲霉氧化还原途径成员的靶向性和抑制作用；3)利用中和抗体和恶二唑化合物在体内消除成虫的氧化还原活性。实验设计包括使PI能够在对未来成功至关重要的领域发展技术技能的方法。该提案特别概述了K22支持将如何通过为科学发展和专业成长提供必要的机会来增强和加强PI以前的研究经验和博士后培训。这项K22奖项的资金将最大限度地发挥PI的潜力，使他成为一名独立的研究员，以便为分子蠕虫学领域做出有意义的贡献。J.Vermeire-项目描述本提案中描述的实验旨在表征钩虫的抗氧化途径以及一类新的先导药物化合物对其活性的影响。这与公众健康直接相关，因为它将提供有关这些酶在寄生虫生物学和宿主疾病中的作用的信息。从这些实验中获得的信息可能直接有助于开发治疗人类钩虫疾病的新药。

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 - Project Narrative The experiments delineated in this proposal are designed to characterize hookworm antioxidant pathways and the effect of a new class of lead drug compounds on their activity. This is directly relevant to public health because it will provide information about the role of these enzymes in parasite biology and host disease. Information gained from these experiments may directly contribute to the development of new drugs for the treatment of human hookworm disease.