Mechanisms of anti-schistosome artemisinin chemotherapy

描述(由申请人提供)： 血吸虫病是一种重要的热带寄生虫病，在70多个国家有超过2亿人感染(Engels等人，2002年)。尽管广泛使用化疗和其他控制策略，但在过去50年中，血吸虫病的传播率几乎没有变化。目前只有一种药物被广泛使用，人们担心会出现抗药性寄生虫(Doenhoff等人，2002年；Cioli和Pica-Mattoccia，2003年)。实验室结果表明，体外选择可能导致抗药性寄生虫(Fall和Doenhoff，1994)。因此，迫切需要开发新的化疗药物来控制血吸虫病。这一探索性/发展性研究提案(即R21)的目标是确定可作为血吸虫病化疗靶点的单个蛋白质或途径。青蒿素是一类新的抗疟疾和抗血吸虫化合物，被认为是通过青蒿素自由基衍生物发挥作用的。这些青蒿素自由基被认为可以使蛋白质中特定氨基酸残基的游离基、氨基和硫基烷基化。人们对青蒿素抗血吸虫的作用机制知之甚少，也没有鉴定出与青蒿素发生反应的血吸虫蛋白。因此，我们的第一个特定目标是：1)利用蛋白质组学方法，在体内和体外对寄生虫进行标记后，确定青蒿素标记的血吸虫蛋白。由于青蒿素对血吸虫具有活性，而血吸虫产生类似于疟原虫的血红素衍生物，我们推测青蒿素对血吸虫的作用也有类似的杀灭机制。因此，这项提案的另外两个目的是为了测试曼氏血吸虫中的青蒿素蛋白靶标是否与疟原虫中已识别的蛋白质靶标同源。我们进一步的具体目标是2。)测定青蒿素对曼氏葡萄球菌Ca-ATPase的药理作用；确定青蒿素是否阻断曼氏血吸虫翻译控制的肿瘤蛋白的组胺释放能力。本研究的关键结论将指导未来青蒿素抗寄生虫活性的分子机制研究。

DESCRIPTION (provided by the applicant): Schistosomiasis is an important tropical parasitic disease with more than two hundred million human infections in more than 70 countries (Engels et al., 2002). In spite of the widespread use of chemotherapy and other control strategies transmission rates of schistosomiasis have changed little over the past 50 years. Currently a single drug is in widespread use and there is concern that drug resistant parasites will appear (Doenhoff et al., 2002; Cioli and Pica-Mattoccia, 2003). Laboratory results indicate that in vitro selection can lead to drug resistant parasites (Fallen and Doenhoff, 1994). Therefore, there is an urgent need for the development of new chemotherapies for the control of schistosomiasis. The goal of this Exploratory/Developmental Research proposal (i.e. R21) is to identify individual proteins or pathways that can be targeted for chemotherapeutic treatment of schistosomiasis. Artemisinins are a new class of antimalarial and antischistosomal compounds that are thought to function via artemisinin radical derivatives. These artemisinin radicals are thought to then alkylate free amino and thiol groups of specific amino acid residues of proteins. Very little is known about mechanisms of action of artemisinins against schistosomes and no schistosome proteins that react with artemisinin have been identified. Therefore, our first specific aim is to 1 ) Determine schistosome proteins labeled by artemisinins after in vivo and in vitro labeling of parasites using proteomic approaches. Because artemisinins are active against schistosomes and schistosomes produce heme derivatives similar to Plasmodium, we hypothesize that similar killing mechanisms will be involved in the action of artemisinins against schistosomes. Therefore, the two additional aims of this proposal are designed to test if artemisinin protein targets in Schistosoma mansoni are homologous to the identified protein targets in Plasmodium. Our further specific aims are to 2.) Determine the pharmacological effect of artemisinin on S. mansoni Ca-ATPases; 3.) Determine whether artemisinins block the histamine releasing ability of S. mansoni translationally controlled tumor protein. The critical conclusions of this study will direct subsequent future experiments into the molecular mechanism of artemisinin's anti-parasitic activity.