The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated by a single drug, praziquantel (PZQ). Although PZQ has served as an effective clinical agent for almost four decades, several features of PZQ are less than ideal including a lack of understanding about the molecular target(s) of this drug. This lack of mechanistic information impedes rational design of alternative therapeutics and is alarming in the face of an inability of PZQ to kill all stages of the parasitic lifecycle, and the emergence of schistosome strains exhibiting refractoriness to PZQ exposure. The long-term goal of this project is to define the target(s) engaged by PZQ in vivo to facilitate development of the next-generation of anthelmintic drugs. This proposal is based upon recent observations that PZQ has been shown to interact with serotonin (5-HT) receptors in the human host. This is an interesting observation as 5-HT signaling regulates contraction of the blood vessels in which the adult blood flukes reside within the mesenteric vasculature. Whether these host vascular interactions contribute to the efficacy of PZQ as a clinical agent, and whether these interactions provide clues to the parasitic target(s) of PZQ are unanswered questions. My graduate training proposal will first focus on defining targets of PZQ in the human host. I will test the hypothesis that PZQ acts as a tryptaminergic pharmacophore in the host, interacting with tryptaminergic binding sites on specific 5-HT G protein coupled receptors (R-PZQ), and transient receptor potential channels (S-PZQ). Having identified the relevant host targets of PZQ (Aim 1), I can then assess whether PZQ interaction with these defined host signaling pathways contributes to the therapeutic effectiveness of this drug (Aim 2). A longer term significance of these activities will be for revealing likely parasitic target(s) of PZQ.
Two Aims are proposed.
In Aim 1, host targets of PZQ enantiomers in the host mesenteric vasculature will be defined using pharmacological and genetic manipulations in conjunction with wire myography to measure the contractile tone of isolated mesenteric arteries.
In Aim 2, the importance of PZQ interactivity with the identified host receptors will be assessed in schistosome-infected mice under conditions where PZQ interactivity with host targets is impaired. Effects on mesenteric blood flow (important for flushing worms to the liver), worm and egg burden, and inflammatory damage in the mouse model of schistosomiasis will be examined. This research is significant, as it will reveal target(s) and pathways engaged by this important therapeutic that have proved unresolved over almost 40 years of clinical use. Successful completion of my project will aid identification of PZQ target(s) and thereby the development of the next generation of antischistosomal drugs.
Schistosomiasis is a parasitic disease afflicting ~200 million people worldwide, causing significant healthcare and welfare burdens in third world countries. Current therapy depends on a single drug (praziquantel) with several non-optimal features: one of these problems is our lack of understanding of how praziquantel works, as no molecular targets have been identified. My research aims to tackle this problem and identify relevant molecular targets of praziquantel in both the human host and parasitic worms, circumventing this long standing roadblock in our field.
