Anthelmintic Compounds Targeting Methyltransferases

The long-term goal of this project is to develop and commercialize anthelmintic drugs to treat nematode infections of animals. Control of parasitic nematode infections in livestock and companion animals is currently dependent on chemical classes discovered more than two decades ago. The economic burden of nematode diseases and the rise of drug-resistant nematodes make it imperative that new effective anthelmintics be brought to market. A significant economic opportunity exists in the area of animal health for the commercialization of novel anthelmintic agents against the most economically important nematode parasites, including Ostertagia in cattle, Haemonchus in sheep, and strongylid infections of horses. Compounds have been identified that target two nematode-specific methyltransferase activities. These enzymes are conserved in many nematodes, play a critical role in the nematode life cycle, and loss of their activity through RNA interference is lethal. The homologous genes are absent from all surveyed vertebrate genomes. More than ten substrate analogs have been identified which are lethal to the free-living nematode C. elegans. The immediate goal of the research is to broaden and improve this family of anthelmintic compounds by designing, synthesizing and testing analogs of the identified inhibitors. Commercially available and newly synthesized compounds will be tested for activity against three free-living nematode species. The most efficacious inhibitors will then be assayed for activity in vitro against animal parasitic nematodes.