Mechanism of praziquantel action at a parasitic flatworm ion channel. Sci Transl Med 2021 Dec 22;13(625):eabj5832
Date
12/23/2021Pubmed ID
34936384Pubmed Central ID
PMC8855674DOI
10.1126/scitranslmed.abj5832Scopus ID
2-s2.0-85122014054 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
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 (TRPMPZQ) 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 TRPMPZQ homologs in other PZQ-sensitive flukes, but not Fasciola hepatica. However, a single amino acid change in the F. hepatica TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved.
Author List
Park SK, Friedrich L, Yahya NA, Rohr CM, Chulkov EG, Maillard D, Rippmann F, Spangenberg T, Marchant JSAuthor
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnthelmintics
Humans
Ion Channels
Platyhelminths
Praziquantel
Schistosoma