Development of IMPDH-Targeted Drugs against Crytosporidium

描述(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源性疫情，包括1993年密尔沃基疫情，约40万人感染了疾病，造成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本可以用少量的努力和简单的设备制备，而且很容易获得供水，因此它被归类为B类生物战剂。免疫功能低下的患者、孕妇和老年人有患严重疾病的风险；艾滋病患者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。我们发现，这种真核病原体通过细菌的水平转移获得了大量的基因。这些细菌基因编码的酶为寄生虫特异性药物的设计提供了高度不同的靶点。其中一种酶是IMP脱氢酶(IMPDH)，它催化鸟嘌呤核苷酸生物合成的关键步骤。使用RO1资助机制，我们验证了IMPDH作为寄生虫治疗的靶点，并确定了10种选择性抑制寄生虫酶的主要命中。在这里，我们提出了一个药物化学计划，以优化这些化合物，并在小鼠感染模型中确定具有抗寄生虫活性的候选药物： 目的1：评估主要目标化合物，并选择四种先导化合物进行优化。 目标2：通过药物化学程序优化四铅系列。 目的3：鉴定隐孢子虫感染动物模型中的高级先导化合物，并选择候选药物。 在选择候选药物后，在本提案中未包括的工作中，我们将执行临床前开发计划，从而向FDA提交IND申请。 如果成功，这项提议中描述的工作将开发一种迫切需要的药物，用于管理疫情爆发和艾滋病患者中的隐孢子虫病，在发生生物恐怖袭击时将是无价的。

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.