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- Title
Mechanism of praziquantel action at a parasitic flatworm ion channel.
- Authors
Park, Sang-Kyu; Friedrich, Lukas; Yahya, Nawal A.; Rohr, Claudia M.; Chulkov, Evgeny G.; Maillard, David; Rippmann, Friedrich; Spangenberg, Thomas; Marchant, Jonathan S.
- Abstract
Praziquantel's Target: Praziquantel (PZQ) is a critical antiparasitic drug used to treat schistosomiasis and other parasitic helminths, but its mechanism has not been resolved. A pair of manuscripts by Park et al. and Le Clec'h et al. identified a Schistosoma mansoni transient receptor potential melastatin ion channel (TRPMPZQ) as the target of PZQ. Park et al. characterized a PZQ binding pocket in TRPMPZQ using ligand-based screening and targeted mutagenesis and confirmed that it was broadly conserved in other parasitic flatworms. Le Clec'h et al. used a genome-wide association screen and marker-assisted selection to identify TRPMPZQ as being responsible for variation in PZQ sensitivity and examine sequence variation in TRPMPZQ from field isolates. Together, these papers robustly confirm that TRPMPZQ is the molecular target of PZQ and provide critical information for monitoring PZQ resistance in the field. 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.
- Subjects
ION channels; PLATYHELMINTHES; CALCIUM channels; TRP channels; PRAZIQUANTEL; FASCIOLA hepatica
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 625, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abj5832