DEVELOPMENT OF NUCLEAR RECEPTORS AS ANTHELMINTIC TARGETS

Over one billion people worldwide are infected by parasitic nematodes that cause various debilitating nutritional, gastrointestinal, and other diseases. Many such infections are not curable with existing medications, and preventive vaccinations are not yet feasible for these complex parasites. The long-term goal of this project is to identify new anti- nematode compounds that will fulfill this human health need. The complete genome sequence of the model free-living nematode Caenorhabditis elegans reveals 260 genes encoding nuclear receptor (NR) transcription factors. The majority of these genes define NR classes unique to nematodes. Many NRs have been fruitful sources of drug therapies. Essential nematode NRs will be promising targets for selective anti-nematode drug discovery efforts. Preliminary data from work with C. elegans has identified NR genes essential for nematode viability. The specific aims for Phase I of this project are: (1) Identify homologues of the essential C. elegans NRs in parasitic nematodes, to validate these NRS as candidate general nematocide targets. (2) Establish cell-based assays for chemical modulators of nematocide NR activity, to provide a foundation for development of high-throughput chemical screens in Phase II. PROPOSED COMMERCIAL APPLICATIONS: The proposed Phase I efforts will establish cell-based assays for the activity of nematode NRs that represent promising biological targets for nematocide development efforts. During Phase II these assays will be adapted for high-throughput screening and extended to additional nematode NRs of interest. The resulting proprietary collection of assays will allow compound screening against a battery of NRs from multiple nematode species. Compounds identified by these screens will represent leads that can be further developed as candidate anthelmintic drugs.