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 et al.，2002年）。尽管广泛使用化疗和其他控制策略，但血吸虫病的传播率在过去50年中变化不大。目前，单一药物被广泛使用，并且担心会出现耐药性寄生虫（Doenhoff等人，2002年; Cioli和Pica-Mattoccia，2003年）。实验室结果表明，体外选择可导致抗药性寄生虫（Fallen和Doenhoff，1994）。因此，迫切需要开发新的化学疗法来控制血吸虫病。本探索性/开发性研究提案（即R21）的目标是确定可用于血吸虫病化疗治疗的单个蛋白质或途径。青蒿素是一类新的抗疟疾和抗寄生虫化合物，被认为通过青蒿素自由基衍生物发挥作用。这些青蒿素自由基被认为然后烷基化蛋白质的特定氨基酸残基的游离氨基和巯基。关于青蒿素对核糖体的作用机制知之甚少，也没有发现与青蒿素反应的核糖体蛋白。因此，我们的第一个具体目标是1）确定青蒿素标记后，在体内和体外标记的寄生虫蛋白质组学方法。由于青蒿素对疟原虫有活性，而疟原虫产生类似于疟原虫的血红素衍生物，因此我们假设青蒿素对疟原虫的作用也涉及类似的杀伤机制。因此，该提案的两个额外目的旨在测试曼氏血吸虫中的青蒿素蛋白质靶标是否与疟原虫中鉴定的蛋白质靶标同源。我们的具体目标是2）。测定青蒿素对S. mansoni Ca-ATP酶; 3.）测定青蒿素是否阻断S. mansoni抑制性肿瘤蛋白。本研究的重要结论将指导今后的实验进入青蒿素的抗寄生虫活性的分子机制。

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.