Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against the liver fluke Fasciola . The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we show PZQ activates a transient receptor potential melastatin ion channel (TRPM PZQ ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage-sensor like domain to cause Ca 2+ entry and worm paralysis. PZQ activates TRPM PZQ homologues in other PZQ-sensitive flukes, but not Fasciola . However, a single amino acid change in the Fasciola TRPM PZQ binding pocket, to mimic schistosome TRPM PZQ , confers PZQ sensitivity. After decades of clinical use, the basis of PZQ action at a druggable TRP channel is resolved.

Mechanism of praziquantel action at a parasitic flatworm ion channel