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Mechanism of praziquantel action at a parasitic flatworm ion channel.

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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.
Source: Science Translational Medicine; 12/22/2021, Vol. 13 Issue 625, p1-8, 8p
Subject Terms: ION channels, PLATYHELMINTHES, CALCIUM channels, TRP channels, PRAZIQUANTEL, FASCIOLA hepatica
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. [ABSTRACT FROM AUTHOR]
Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Mechanism of praziquantel action at a parasitic flatworm ion channel.
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  Data: <searchLink fieldCode="AR" term="%22Park%2C+Sang-Kyu%22">Park, Sang-Kyu</searchLink><br /><searchLink fieldCode="AR" term="%22Friedrich%2C+Lukas%22">Friedrich, Lukas</searchLink><br /><searchLink fieldCode="AR" term="%22Yahya%2C+Nawal+A%2E%22">Yahya, Nawal A.</searchLink><br /><searchLink fieldCode="AR" term="%22Rohr%2C+Claudia+M%2E%22">Rohr, Claudia M.</searchLink><br /><searchLink fieldCode="AR" term="%22Chulkov%2C+Evgeny+G%2E%22">Chulkov, Evgeny G.</searchLink><br /><searchLink fieldCode="AR" term="%22Maillard%2C+David%22">Maillard, David</searchLink><br /><searchLink fieldCode="AR" term="%22Rippmann%2C+Friedrich%22">Rippmann, Friedrich</searchLink><br /><searchLink fieldCode="AR" term="%22Spangenberg%2C+Thomas%22">Spangenberg, Thomas</searchLink><br /><searchLink fieldCode="AR" term="%22Marchant%2C+Jonathan+S%2E%22">Marchant, Jonathan S.</searchLink>
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  Data: Science Translational Medicine; 12/22/2021, Vol. 13 Issue 625, p1-8, 8p
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  Data: <searchLink fieldCode="DE" term="%22ION+channels%22">ION channels</searchLink><br /><searchLink fieldCode="DE" term="%22PLATYHELMINTHES%22">PLATYHELMINTHES</searchLink><br /><searchLink fieldCode="DE" term="%22CALCIUM+channels%22">CALCIUM channels</searchLink><br /><searchLink fieldCode="DE" term="%22TRP+channels%22">TRP channels</searchLink><br /><searchLink fieldCode="DE" term="%22PRAZIQUANTEL%22">PRAZIQUANTEL</searchLink><br /><searchLink fieldCode="DE" term="%22FASCIOLA+hepatica%22">FASCIOLA hepatica</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 (TRPM<subscript>PZQ</subscript>) as the target of PZQ. Park et al. characterized a PZQ binding pocket in TRPM<subscript>PZQ</subscript> 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 TRPM<subscript>PZQ</subscript> as being responsible for variation in PZQ sensitivity and examine sequence variation in TRPM<subscript>PZQ</subscript> from field isolates. Together, these papers robustly confirm that TRPM<subscript>PZQ</subscript> 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 (TRPM<subscript>PZQ</subscript>) 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<subscript>PZQ</subscript> homologs in other PZQ-sensitive flukes, but not Fasciola hepatica. However, a single amino acid change in the F. hepatica TRPM<subscript>PZQ</subscript> binding pocket, to mimic schistosome TRPM<subscript>PZQ</subscript>, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/scitranslmed.abj5832
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        Text: English
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    Subjects:
      – SubjectFull: ION channels
        Type: general
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              Text: 12/22/2021
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