Targeting Host and Apicomplexan Isoprenoid Pathways

描述（由申请人提供）：顶复合体是重要的病原体，包括疟疾、弓形虫病和隐孢子虫病的病原体。刚地弓形虫是人类弓形虫病的病原体，这是一种全身性感染，主要通过受污染的水和蔬菜或未煮熟的肉类获得。组织囊肿的形成发生在感染后不久，并负责终身感染免疫正常的个体。世界上至少有三分之一的人口和约22.5%的美国人对弓形虫病呈血清阳性反应，使其成为美国最普遍的感染之一。弓形虫居住在寄生液泡内的细胞内，免疫抑制后可能发生感染的再激活和传播到不同器官。小隐孢子虫对发展中国家的儿童造成了重大的疾病负担，并可导致艾滋病患者患上危及生命的慢性肠炎。目前对弓形虫慢性感染和隐孢子虫病的化疗效果不佳，迫切需要治疗这两种感染的新药。刚地弓形虫缺乏甲羟戊酸途径合成类异戊二烯前体，但在其顶质体中含有1-脱氧-d -木醛糖-5-磷酸（DOXP）途径。该途径生成二磷酸异戊烯基（IPP）和二磷酸二甲基基（DMAPP），通过独特的法尼酯二磷酸合成酶（TgFPPS）缩合成法尼酯二磷酸（FPP）和香叶基二磷酸（GGPP）。我们的初步数据表明，DOXP途径对弓形虫在宿主体内的存活至关重要。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，在体外和体内都对寄生虫有活性。这些结果表明

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.