Targeting Host and Apicomplexan Isoprenoid Pathways

描述（由申请人提供）：顶复门是重要的病原体，包括疟疾、弓形体病和隐孢子虫病的病原体。弓形虫是人类弓形虫病的病原体，弓形虫病是一种全身性感染，主要通过受污染的水和蔬菜或生肉获得。组织囊肿的形成发生后不久，感染和负责终身感染的免疫功能正常的个人。至少三分之一的世界人口和大约22.5%的美国人对弓形虫病呈血清阳性，使其成为美国最流行的感染之一。T.弓形虫存在于细胞内的寄生虫空泡内，免疫抑制后可能发生感染的再激活和传播到不同器官。隐孢子虫是发展中国家儿童的重大疾病负担，它可以导致艾滋病患者慢性和危及生命的肠炎。目前对T.弓形虫慢性感染和隐孢子虫病是无效的，迫切需要新的药物来治疗这两种感染。 T.刚地缺乏合成类异戊二烯前体的甲羟戊酸途径，但在其顶质体中具有1-脱氧-D-木酮糖-5-磷酸（DOXP）途径。该途径产生异戊烯基二磷酸（IPP）和二甲基烯丙基二磷酸（DMAPP），它们通过独特的法呢基二磷酸合酶（TgFPPS）的作用缩合成法呢基二磷酸（FPP）和香叶基香叶基二磷酸（GGPP）。我们的初步数据表明，DOXP途径是T。弓形虫在宿主体内存活。然而，令人惊讶的是，作用于甲羟戊酸途径的药物，如他汀类药物，在体外和体内对寄生虫都有活性。这些结果表明 寄生虫需要合成一些类异戊二烯前体（IPP，DMAPP），同时从其宿主中回收其他类异戊二烯前体（FPP，GGPP）。我们将利用这一点制定一个双重打击战略。值得注意的是，该模型表明隐孢子虫应该对这种方法非常敏感。 公共卫生相关性：我们的目标是找到干扰弓形虫代谢途径的方法，作为控制由这种和类似寄生虫引起的感染的策略。我们已经确定类异戊二烯途径是T.刚地。寄生虫合成类异戊二烯中间体并从其宿主中摄取一些。基于我们的研究结果，我们提出了一种结合宿主和寄生虫类异戊二烯途径抑制剂的策略。在项目的第二阶段，我们将调整这一战略的休眠阶段的T。弓形虫和其它寄生虫如隐孢子虫。

DESCRIPTION (provided by applicant): Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Toxoplasma gondii is the causative agent of human toxoplasmosis, a systemic infection acquired mostly through contaminated water and vegetables, or uncooked meat. Tissue cyst formation occurs soon after infection and is responsible for lifelong infection in immunocompetent individuals. At least one-third of the World's population and about 22.5% of Americans are seropositive for toxoplasmosis, making it one of the most prevalent infections in the United States. T. gondii resides intracellularly within parasitophorous vacuoles, and reactivation and dissemination of infection to different organs may occur following immune suppression. Cryptosporidium parvum is responsible for significant disease burden among children in developing countries and it can result in chronic and life-threatening enteritis in AIDS patients. The present chemotherapy available against T. gondii chronic infection and cryptosporidiosis is not effective and new drugs are urgently needed to treat both infections. T. gondii lacks a mevalonate pathway for the synthesis of isoprenoid precursors but harbor a 1-deoxy-D- xylulose-5-phosphate (DOXP) pathway in its apicoplast. This pathway generates isopentenyl diphosphate (IPP) and dimethyallyl diphosphate (DMAPP), which are condensed by the action of a unique farnesyl diphosphate synthase (TgFPPS) into farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP). Our preliminary data have indicated that the DOXP pathway is essential for T. gondii survival in its host. Surprisingly, though, drugs acting on the mevalonate pathway, like statins, are active in vitro and in vivo against the parasite. These results indicate that the parasite needs to synthesize some isoprenoid precursors (IPP, DMAPP), while salvaging others (FPP, GGPP) from its host. We will exploit this to develop a double hit strategy. Remarkably the model suggests that Cryptosporidium parvum should be highly susceptible to this approach. PUBLIC HEALTH RELEVANCE: Our goal is to find ways of interfering with Toxoplasma gondii metabolic pathways as a strategy for controlling infections caused by this and similar parasites. We have identified that the isoprenoid pathway is essential for T. gondii. The parasite synthesizes isoprenoid intermediates and takes up some from its host. Based on our results, we propose a strategy of combining inhibitors of both host and parasite isoprenoid pathways. In the second phase of the project we will adapt this strategy to dormant stages of T. gondii, and to other parasites such as Cryptosporidium.