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