Resolving the properties of schistosome TRPMPZQ, the target of the anthelmintic drug praziquantel

Medical College Of Wisconsin, Milwaukee WI

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Abstract

PROJECT SUMMARY The parasitic infection schistosomiasis afflicts over 250 million people worldwide and is clinically treated using a single drug, praziquantel (PZQ). Although PZQ has served as a stalwart anthelmintic for decades, the molecular basis of action of this drug has remained undefined since the 1970s. The lack of mechanistic knowledge about the parasite target of PZQ has impeded the field from realizing the advantages that identification of a validated drug target confers. These include rational design of improved therapeutics, as well as genomic surveillance of a likely locus for drug resistance. In the current R01 funding period, our laboratory finally identified the parasite target of PZQ. This was revealed as a transient receptor potential ion channel of the melastatin subfamily, named TRPMPZQ. TRPMPZQ is present in all parasitic flatworms and variation in the sensitivity of TRPMPZQ orthologs between parasites correlated with the different clinical dosing of PZQ needed to cure specific infections. Our work also revealed a distinct ion channel within the same TRPM subfamily as an unexpected target for another anthelmintic. Consequently, the premise of this proposal is that TRPM family members have recently emerged as validated, prosecutable targets with potential to deliver new treatments for infections caused by parasitic flatworms. Our work discovering the parasite targets of these orphan anthelmintic ligands provides new opportunity to tackle critical questions in our field. These are: (i) Understanding why PZQ displays poor efficacy against juvenile worms, often underpinning poor rates of infection clearance, so that we improve PZQ effectiveness against all life cycle stages (Aim 1); (ii) Defining the molecular basis by which parasite life cycle stages transition between different environments and hosts during the schistosome lifecycle (Aim 2), and (iii) Dissecting the molecular pathways that may underpin PZQ resistance in the field (Aim 3). To tackle this triad of challenges, we have assembled a multi-PI team of investigators who bring together unique skills spanning expertise in protein structure determination (Liu), molecular parasitology (Marchant) and genomic analyses of variation (Riehle). If successful, our work will dissect TRPMPZQ regulation at the physiological and genetic level to help accelerate development of next generation anthelmintics active against all parasite life cycle stages. Our work brings translational impact for public health by aiding surveillance of PZQ efficacy in the field, as any decline in the effectiveness of PZQ as a clinical therapy would prove a huge public health challenge, impairing WHO goals to drive this infectious disease toward elimination.