Ecdysteroid Signaling in Filarial Parasites

描述(申请人提供)：由人类丝虫寄生虫引起的疾病是一个严重的全球卫生问题。这些疾病的巨大社会经济影响引起了国际社会的关注，国际社会支持了几个控制这些感染的方案。这些方案依赖于数量非常有限的药物的大规模分发，所有这些药物都必须在一段时间内重复给予以控制传播，因为它们主要影响寄生虫的幼虫阶段(微丝虫)。长期重复治疗的需要在后勤上是困难的，如果出现耐药性，这些计划很容易失败。因此，显然需要新药来补充现有的微丝杀菌剂。实验和临床证据表明，针对成年女性生殖过程的药物，导致绝育，将特别 令人向往。丝虫被归类为蜕皮虫，其发育的特征是从一个阶段到另一个阶段的一系列蜕皮。大多数关于蜕皮虫发育的研究都集中在昆虫上。昆虫的中央发育调节因子是蜕皮激素受体(ECR)，它除了控制蜕皮外，还在胚胎发生和其他发育过程中发挥作用。ECR已被农业行业用作目标，他们开发了对目标昆虫毒性很大但对脊椎动物无毒的杀虫蜕皮酮类似物。我们最近合作从人类丝虫寄生虫B.marayi中鉴定出ECR的同源物。这是涉及的第一个已定义的监管机构 丝虫发育。成功开发出对非目标生物体无毒的高效ECR类似物杀虫剂，突显了ECR作为人类丝虫感染化疗靶标的潜力。此外，间接证据表明蜕皮激素可能在丝虫胚胎发生中起重要作用，这表明靶向ECR的化合物可能扰乱寄生虫的繁殖。该项目的总体目标将是调查丝虫ECR作为化疗靶点的潜力。为了实现这一目标，我们提出了以下具体目标：1.将我们现有的方法调整为高通量筛选模式，以鉴定马来双胞菌蜕皮激素受体(BmEcR)的激动剂和拮抗剂。2.筛选BmEcR激动剂和拮抗剂的天然产物文库和两个蜕皮激素类似物库。3.评价先导BmEcR激动剂和拮抗剂对体外培养马来丝虫的作用。

DESCRIPTION (provided by applicant): Diseases caused by the human filarial parasites are a serious global health problem. The large socio- economic impact of these diseases has attracted the attention of the international community, which has supported several programs to control these infections. These programs rely upon mass distribution of a very limited number of drugs, all of which must be given repeatedly over a period of years to control transmission, as they primarily affect the larval stage of the parasite (the microfilariae). The need for prolonged repeated treatment is logistically difficult and leaves the programs vulnerable to failure if resistance develops. Thus, there is a clear need for new drugs to supplement the microfilaricides currently available. Experimental and clinical evidence suggest that drugs that target the adult female's reproductive processes, resulting in sterilization, would be particularly desirable. Filaria are classified as ecdysozoans, organisms whose development is characterized by a series of molts from one stage to another. Most studies of ecdysozoan development have concentrated on insects. A central developmental regulator in insects is the ecdysone receptor (EcR), which plays a role in embryogenesis and other developmental processes, in addition to controlling molting. The EcR has been exploited as a target by the agricultural industry, which has developed insecticidal ecdysone analogs that are very toxic to their target insects but non-toxic to vertebrates. We have recently collaborated on the identification of a homolog of the EcR from the human filarial parasite B. malayi. This represents the first defined regulator involved in filarial development. The success in developing highly effective EcR analog insecticides which are non-toxic to off-target organisms underscores the potential of the EcR as a chemotherapeutic target for human filarial infections. Furthermore, the indirect evidence suggesting that ecdysteroids may be important in filarial embryogenesis suggests that compounds targeting the EcR may disrupt parasite reproduction. The overall goal of this project will be to investigate the potential of the filarial EcR as a chemotherapeutic target. To accomplish this goal, we propose the following specific aims: 1. To adapt our existing assay to a high throughput screening format for identification of agonists and antagonists of the B. malayi ecdysone receptor (BmEcR). 2. To screen a natural products library and two ecdysteroid analog libraries for BmEcR agonists and antagonists. 3. To evaluate the effect of the lead BmEcR agonists and antagonists on B. malayi parasites in culture.