Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer-(R)-PZQ-which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.
Bibliographical noteFunding Information:
Schistosome-infected mice were provided by the NIAID Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, MD) through NIH-NIAID Contract HHSN272201000005I for distribution through BEI Resources. Work was supported by the NIH (GM088790, R21AI25821, R21AI130642 to J.S.M.; RO1MH61887 to J.D.M. and B.L.R.; R01AI087807 to C.C., T.R.W. and P.M.C.), NSF (MCB1615538 to J.S.M.) and the National Institute of Mental Health’s Psychoactive Drug Screening Program PDSP screening program, contract #HHSN-271-2013-00017-C (NIMH PDSP). We thank Joyce Lee, Nawal Yahya and Jonathan Wojcik for their assistance preparing this work.