Identification of novel anthelmintics through a target-based screen of a parasite ion channel

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PROJECT SUMMARY Over a third of the world's population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. The mainstay pharmacotherapy for schistosomiasis, and several other parasitic helminth infections, is the drug praziquantel (PZQ). However, several features of PZQ are severely limiting. These include an inability of PZQ to kill all stages of the parasitic life cycle, clinical reliance on PZQ as a monotherapy in light of sub-optimal cure rates and field reports of PZQ resistance, as well as an inability to improve upon the PZQ pharmacophore or define mechanistically how this drug works. Consequently, there is a need to develop next generation anthelmintics, ideally active against a broad spectrum of PZQ-sensitive helminth parasites. Our laboratory has provided new critical insight by discovering the target of PZQ in parasitic schistosomes [1, 2]. We recently identified a Ca2+-permeable transient receptor potential (TRP) ion channel (Sm.TRPMPZQ) in Schistosoma mansoni that reproduces the characteristics of PZQ action on schistosomes: nanomolar potency, stereoselectivity for (R)-PZQ, and mediation of a sustained, cytotoxic Ca2+ entry [1, 2]. With this target in hand, it is now possible to conduct a screening campaign to identify novel ligands/regulators of this channel with potential as next generation anthelmintics. Therefore, to build upon this breakthrough, we have assembled a team combining expertise in high throughput screening (HTS), lead prioritization and optimization (Scripps Florida), together with in-house expertise in parasitic flatworm biology (Medical College of Wisconsin, MCW). This team will (i) execute a primary screen against Sm.TRPMPZQ (Scripps Florida) and (ii) validate the resulting hits for efficacy against parasitic schistosome worms ex vivo, and in vivo using a murine model of schistosomiasis infection (MCW). Prioritized hits will also be evaluated against other species of schistosome worms, and in the longer term other parasitic flatworms with clinical relevance. A pilot screen and validation data presented as preliminary data support the rigor of target identification, assay optimization and miniaturization, and feasibility of the proposed pipeline for hit validation. The proposed activities have relevance to this FOA by supporting (i) the identification of novel small molecules with potential to treat infectious diseases and (ii) generation of new insight into the biology of parasite TRP ion channels, which have received little attention to date as novel drug targets. If successful, these activities will provide new leads with potential for usage as next generation antiparasitics.