IMPDH as a Drug Target in Cryptosporidium

IMPDH 作为隐孢子虫的药物靶点

• 批准号: 6984118
• 负责人: BORIS STRIEPEN
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984118
• 关键词: Cryptosporidium; SCID mouse; Toxoplasma gondii; X ray crystallography; alcohol oxidoreductases; drug discovery /isolation; drug screening /evaluation; high throughput technology; inosine monophosphate; oxidoreductase inhibitor; purine /pyrimidine metabolism; purine nucleosides; tissue /cell culture

DESCRIPTION (provided by applicant): Cryptosporidium parvum is a protozoan parasite that causes severe disease in small children, pregnant women, the elderly, and those with a weakened immune system and contributes significantly to morbidity and mortality among AIDS patients. C. parvum is resistant to many water disinfection procedures and several large outbreaks in the US have been linked to drinking and recreational water contamination. There is a growing and credible concern that this organism could be deliberately introduced into the water supply in an act of bioterrorism. The tools to react to such an incident are woefully inadequate; no vaccine and no effective drug treatment are available for Cryptosporidium. New drugs are clearly needed to face this threat. C. parvum, like all parasitic protozoa, is entirely dependent on purine salvage from the host, making this pathway an extremely attractive drug target. We will delineate the purine uptake and salvage pathways of C. parvum. Our Preliminary Results suggest that inosine-5'-monophosphate-dehydrogenase (IMPDH) is a key enzyme in these pathways. IMPDH is a validated and clinically used drug target. Large and growing libraries of potential inhibitors are already available. This application proposes to study the biochemistry of IMPDH from C. parvum and to screen for potential lead inhibitors from existing compound libraries. Importantly, the peculiar 'extracytoplasmatic' position of the parasite within the infected cell has been associated with its resistance to many drugs. We will use C. parvum as well as suitable transgenic models to study the mechanisms of uptake and activation of nucleoside inhibitors. This work will provide urgently needed molecular reagents to understand the biology of nutrient uptake and drug resistance in this unique parasite.

描述（由申请人提供）：隐孢子虫是一种原生动物寄生虫，可导致小儿童，孕妇，老年人以及免疫系统弱的人，并对艾滋病患者的发病率和死亡产生重大贡献。 C. parvum对许多水消毒程序具有抵抗力，在美国进行了几次大规模暴发与饮酒和休闲水污染有关。人们越来越担心这种生物可以在生物恐怖主义行为中故意将其引入供水。对这种事件的反应工具严重不足；没有疫苗和有效的药物治疗可用于隐孢子虫。显然需要新药才能面对这种威胁。像所有寄生原生动物一样，C. parvum完全取决于宿主的嘌呤挽救，这使该途径成为极具吸引力的药物靶标。我们将描述C. parvum的嘌呤摄取和挽救途径。我们的初步结果表明，肌苷-5'单磷酸二氢酶（IMPDH）是这些途径中的关键酶。 IMPDH是经过验证且临床使用的药物靶标。潜在抑制剂的大型且不断增长的图书馆已经可用。该申请建议从C. parvum研究IMPDH的生物化学，并筛选现有化合物库的潜在铅抑制剂。重要的是，寄生虫在感染细胞中的特殊“外质”位置与其对许多药物的抗性有关。我们将使用C. parvum以及合适的转基因模型来研究摄取机制和核苷抑制剂的激活。这项工作将提供急需的分子试剂，以了解这种独特的寄生虫中营养摄取和耐药性的生物学。