Cholinergic Receptors as Targets for Accelerated Anthelmintic Discovery

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DESCRIPTION (provided by applicant): Neglected Tropical Diseases (NTDs) caused by helminths (nematodes and flatworms) perpetuate socioeconomic instability in profoundly impoverished developing countries, inflicting crippling morbidity and/or significant mortality. The prevalence of helminth disease is staggering. Lymphatic filariasis is caused by nematodes including Brugia malayi and afflicts over 120 million people worldwide with over 1.2 billion at risk in 81 disease endemic countries. Schistosomes, the etiological agents of schistosomiasis, are the most pathogenic flatworms, infecting over 200 million with more than 650 million at risk. The lynchpin of NTD control efforts for the foreseeable future will remain the administration of anthelmintic drugs - but worryingly few effective drugs exist, hampering these control strategies. Thus there is a pressing need for new, more effective chemotherapies. Compounding the problem is the reticence of the pharmaceutical industry to engage this need for NTD drugs without the motivation of a financial incentive. This application aims to address this problem by proposing a paradigm shift in the way we discover and develop drugs for NTDs. We propose an innovative Public-Private Partnership between academic laboratories at Iowa State University and McGill University, and Pfizer, Inc. The academic laboratories will invest their time and resources in the molecular identification and validation of potential novel drug targets. Pfizer Animal Health (PAH) will advance selected validated lead targets for mechanism-based screening. The lead targets forming the substrate of this proposal are G protein-coupled acetylcholine receptors and acetylcholine-gated chloride channels in the parasitic nematode B. malayi and the parasitic flatworm Schistosoma mansoni. The first phase of the project will take place in the academic laboratories and will show that drugs acting on these receptors have potential as novel anthelmintics. The experiments will combine bioimaging techniques, RNA interference (RNAi), bioassays, physiology and pharmacology to determine which of these receptors will progress to the next phase of the project at PAH. Here selected receptors will be screened, at PAH expense, against a vast compound library amongst which, we believe, will be small molecules with activity at our receptors. The promise of these active compounds as antiparasitic drugs will be explored both in the academic laboratories and in-house at PAH, subject to material transfers agreement and compound availability. Successful completion of this project will have a truly significant impact on the development of new anthelmintic drugs and has the potential to positively impact the health of hundreds of millions of people worldwide. Further, we will greatly advance our understanding of basic worm biology and address some important knowledge gaps in our understanding of nematode and flatworm physiology and function.