Targeting Host and Apicomplexan Isoprenoid Pathways

摘要 尖端复合体是重要的病原体，包括疟疾、弓形虫病和 隐孢子虫病。弓形虫是人类弓形虫病的病原体，是一种系统性感染。 主要通过受污染的水和蔬菜或未煮熟的肉类获得。组织囊肿形成 在感染后不久发生，并对具有免疫能力的人的终身感染负责。至少 世界上三分之一的人口和大约22.5%的美国人的弓形虫病血清阳性， 使其成为美国最流行的感染之一。弓形虫在细胞内存在于 可能会发生寄生性空泡，并重新激活和将感染传播到不同的器官 在免疫抑制之后。微小隐孢子虫是造成重大疾病负担的原因之一 这可能会导致艾滋病患者患上危及生命的慢性肠炎。 目前可用于治疗弓形虫慢性感染和隐孢子虫病的化疗并不有效。 迫切需要新药来治疗这两种感染。 弓形虫缺乏合成类异戊二烯前体的甲戊酸途径，但含有1-脱氧-D- 其质外体中的木糖-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)，它们通过独特的法尼基的作用而缩合 二磷酸合成酶(TgFPPS)合成法尼基二磷酸(FPP)和香叶基二磷酸(GGPP)。 我们的初步数据表明，DOXP途径对于弓形虫在宿主中的生存是必不可少的。 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，在体外和体内都是有效的 对抗寄生虫。这些结果表明，寄生虫需要合成一些类异戊二烯。 前体(IPP、DMAPP)，同时从宿主中抢救其他前体(FPP、GGPP)。我们将利用这一点来发展 一种双重打击策略。值得注意的是，该模型表明微小隐孢子虫应该高度 容易受到这种方法的影响。

Abstract 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.