Mechanism of praziquantel action at a parasitic flatworm ion channel.

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Park SK, Friedrich L, Yahya NA, Rohr CM, Chulkov EG, Maillard D, Rippmann F, Spangenberg T, Marchant JS

Mechanism of praziquantel action at a parasitic flatworm ion channel.

Sci Transl Med. 2021 Dec 22;13(625):eabj5832. doi: 10.1126/scitranslmed.abj5832. Epub 2021 Dec 22.

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34936384 [ View in PubMed
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Abstract

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 liver flukes of the Fasciola genus. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we use ligand- and target-based methods to demonstrate that 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 of the channel to cause calcium entry and worm paralysis. PZQ activates TRPM(PZQ) homologs in other PZQ-sensitive flukes, but not Fasciola hepatica. However, a single amino acid change in the F. hepatica TRPM(PZQ) binding pocket, to mimic schistosome TRPM(PZQ), confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved.

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