The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPMPZQ Orthologs

The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPMPZQ, has recently bee...

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Veröffentlicht in:ACS medicinal chemistry letters 2023-11, Vol.14 (11), p.1537-1543
Hauptverfasser: Sprague, Daniel J, Kaethner, Marc, Park, Sang-Kyu, Rohr, Claudia M, Harris, Jade L, Maillard, David, Spangenberg, Thomas, Lundström-Stadelmann, Britta, Marchant, Jonathan S
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container_end_page 1543
container_issue 11
container_start_page 1537
container_title ACS medicinal chemistry letters
container_volume 14
creator Sprague, Daniel J
Kaethner, Marc
Park, Sang-Kyu
Rohr, Claudia M
Harris, Jade L
Maillard, David
Spangenberg, Thomas
Lundström-Stadelmann, Britta
Marchant, Jonathan S
description The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPMPZQ, has recently been identified. Intriguingly, certain praziquantel derivatives show different activities against different parasites: for example, some praziquantel analogs are considerably more active against cestodes than against schistosomes. Here we interrogate whether the different activities of praziquantel analogs against different parasites are also reflected by unique structure-activity relationships at the TRPMPZQ channels found in these different organisms. To do this, several praziquantel analogs were synthesized and functionally profiled against schistosome and cestode TRPMPZQ channels. Data demonstrate that structure-activity relationships are closely mirrored between parasites and their TRPMPZQ orthologs, providing further support for TRPMPZQ as the therapeutically relevant target of praziquantel.
doi_str_mv 10.1021/acsmedchemlett.3c00350
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title The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPMPZQ Orthologs
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