Mechanism of Praziquantel Action at a Transient Receptor Potential Channel

The drug praziquantel (PZQ) is an essential medicine for treating schistosomiasis, a parasitic disease that afflicts over 250 million people worldwide. PZQ causes rapid paralysis of the blood flukes cause however flatworm target has been undefined since was discovered in 1970s. Analysis structure-activity relationship (SAR) series >40 analogues revealed SAR these compounds at causing worm mirrored activation schistosome transient receptor potential melastatin ion channel (Sm.TRPMPZQ) vitro. Here, we coalesced ligand- and target-based approaches together with computational modelling to characterize structural basis association Sm.TRPMPZQ. Mutagenesis modeling Sm.TRPMPZQ occurred directly through engagement hydrophobic ligand binding pocket within voltage-sensor like domain (transmembrane helical segments, S1-S4) single point mutations ablate responsiveness PZQ. significance changes context reports decreased effectiveness field, or lower sensitivity isolated strains PZQ, key interest given critical need preserve this burdensome NTD. Therefore, after 40 years clinical usage, established as direct TRP definition site on physiologically relevant target.