Development of IMPDH-Targeted Drugs against Crytosporidium

描述（由申请人提供）：原生动物寄生虫隐孢子虫在美国引起了大规模的水传播疫情，包括1993年密尔沃基的疫情，约40万人感染了疾病，造成了3170万美元的医疗费用和6460万美元的生产力损失。高度浓缩的隐孢子虫样品可以用适当的努力和简单的设备制备，并且很容易获得供水，导致其被列为B类生物战剂。免疫功能低下的病人、孕妇和老年人有患严重疾病的危险；对艾滋病患者来说，感染可能是慢性和致命的。应对此类事件的工具严重不足：目前没有疫苗或有效的药物治疗。我们已经发现这种真核病原体通过细菌的水平转移获得了许多基因。这些细菌基因编码的酶为设计寄生虫特异性药物提供了高度不同的靶点。其中一种酶是IMP脱氢酶（IMPDH），它催化了鸟嘌呤核苷酸生物合成的关键步骤。利用RO1资助机制，我们已经验证了IMPDH作为寄生虫治疗的靶点，并确定了10个选择性抑制寄生虫酶的原则hit。在这里，我们提出了一个药物化学程序来优化这些化合物，并在小鼠感染模型中鉴定出具有抗寄生虫活性的候选药物。

DESCRIPTION (provided by applicant): The protozoan parasite Cryptosporidium has caused massive waterborne outbreaks in the U.S, including the 1993 Milwaukee outbreak, where ~400,000 individuals contracted disease, with an economic cost of $31.7 million in medical expenses and another $64.6 million in productivity losses. Highly concentrated Cryptosporidium samples can be prepared with modest effort and simple equipment, and the water supply is easily accessed, leading to its classification as a category B bio-warfare agent. Immunocompromised patients, pregnant women and the elderly are at risk of serious disease; infection can be chronic and fatal in AIDS patients. The tools to respond to such an incident are woefully inadequate: no vaccine or effective drug treatment is currently available. We have discovered that this eukaryotic pathogen has obtained numerous genes by horizontal transfer from bacteria. The enzymes encoded by these bacterial genes provide highly divergent targets for the design of parasite-specific drugs. One such enzyme is IMP dehydrogenase (IMPDH), which catalyzes a key step in guanine nucleotide biosynthesis. Using the RO1 funding mechanism, we have validated IMPDH as a target for parasite treatment and identified ten Principle Hits that selectively inhibit the parasite enzyme. Here we propose a medicinal chemistry program to optimize these compounds and identify a drug candidate with antiparasitic activity in a mouse model of infection: Aim 1: Assess principal hits and select four lead compounds for optimization. Aim 2: Optimize four Lead Series through a medicinal chemistry program. Aim 3: Characterize Advanced Leads in an animal model of Cryptosporidium infection and chose a drug candidate. Following selection of the Drug Candidate, and in work not included in this proposal, we will execute a Pre- Clinical Development Plan leading to submission of an IND application to the FDA. If successful, the work described in this proposal will develop an urgently needed drug for the management of cryptosporidiosis in epidemic outbreaks and AIDS patients that will be invaluable in the event of a bioterrorist attack.