Ecdysteroid Signaling in Filarial Parasites

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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.