Parasitic blood flukes (flatworms of the genus Schistosoma) cause the neglected topical disease schistosomiasis. This disease infects over 200 million people worldwide, but is clinically treated by just a single drug, praziquantel, whose molecular mechanism of action remains poorly understood despite nearly four decades of use. The vast scope of this infection and the prospect of emerging treatment-resistant strains of schistosome parasites highlight the need for alternative therapeutics. Therefore, the goal of this project is to identify new anti-schistosomal druggable targets and lead compounds. This research will focus on established regulators of flatworm neuromuscular function, bioaminergic neurotransmitters (serotonin and dopamine). It is known that these signals regulate flatworm movement; subverting them by chemical or genetic means results in paralysis or spastic hypermobility. However, the precise receptors governing these phenotypes remain poorly characterized, and, lacking a defined target, no large scale drug screening efforts have been attempted to explore new anti-parasitic compounds. The proposed study will address these deficits by pursuing three, inter-related specific aims: (1) Characterize flatworm bioaminergic receptors that impair mobility. The precise G-protein coupled receptors (GPCRs) that mediate bioaminergic neurotransmission and flatworm neuromusculature will be identified by characterizing isoforms present in a free-living (non-parasitic) planarian. Using this model will enable functional screening by RNAi. Following knockdown of each GPCR, animals will be screened for movement defects, and the schistosome homologs of receptors exhibiting loss of function phenotypes will be expressed in mammalian cells lines for pharmacological profiling. (2) Identify high affinity ligands for Schistosoma mansoni bioaminergic GPCRs through targeted drug screens. Recombinantly expressed schistosome bioaminergic receptors will be interrogated by medium and high throughput screens to identify small molecules capable of subverting bioaminergic signaling. (3) Evaluate efficacy of lead compounds against S. mansoni parasites. Parasite assays will validate the ability of compounds prioritized during in vitro assays to disrupt schistosome movement. Efficacious drugs will be administered to a mouse model of schistosomiasis to determine anti-parasitic effects in vivo. In summary, these aims will functionally screen bioaminergic GPCRs in free-living flatworms, advance recombinantly expressed targets to large scale screening assays, and validate hits for efficacy against parasitic schistosomes. These studies are innovative in executing the first of its kind high-throughput screen against a flatworm drug target. This work will seed the drug discovery pipeline with new targets and lead compounds to combat this neglected human parasite. The proposed work will apply my PhD training in Pharmacology to the disciplines of Parasitology and Medicinal Chemistry, giving me hands on training in drug discovery for human parasites.
One in three people worldwide is infected with a parasitic worm, and the most devastating of these are the blood flukes which cause the neglected tropical disease schistosomiasis. Despite this public health burden, there is currently only one broad spectrum drug available to treat the disease (praziquantel), and it?s mechanism of action is poorly understood. The proposed research will examine the signaling pathways governing flatworm neuromuscular function by performing chemical and genetic screens to advance new targets and candidate therapeutics to treat schistosomiasis.
| Chan, John D; Cupit, Pauline M; Gunaratne, Gihan S et al. (2017) The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand. Nat Commun 8:1910 |
