Sprague Daniel J, Kaethner Marc, Park Sang-Kyu, Rohr Claudia M, Harris Jade L, Maillard David, Spangenberg Thomas, Lundström-Stadelmann Britta, Marchant Jonathan S
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Program in Chemical Biology, Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
ACS Med Chem Lett. 2023 Oct 25;14(11):1537-1543. doi: 10.1021/acsmedchemlett.3c00350. eCollection 2023 Nov 9.
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 TRPM, 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 TRPM channels found in these different organisms. To do this, several praziquantel analogs were synthesized and functionally profiled against schistosome and cestode TRPM channels. Data demonstrate that structure-activity relationships are closely mirrored between parasites and their TRPM orthologs, providing further support for TRPM as the therapeutically relevant target of praziquantel.
抗蠕虫药物吡喹酮仍然是治疗由寄生扁虫引起的各种疾病的关键临床疗法。尽管吡喹酮在临床上长期使用，但其寄生虫靶点仍未明确，不过最近已鉴定出一个名为TRPM的候选离子通道靶点。有趣的是，某些吡喹酮衍生物对不同寄生虫表现出不同的活性：例如，一些吡喹酮类似物对绦虫的活性比对血吸虫的活性高得多。在这里，我们探究吡喹酮类似物对不同寄生虫的不同活性是否也体现在这些不同生物体中发现的TRPM通道独特的构效关系上。为此，合成了几种吡喹酮类似物，并针对血吸虫和绦虫的TRPM通道进行了功能分析。数据表明，寄生虫与其TRPM直系同源物之间的构效关系密切对应，这为TRPM作为吡喹酮的治疗相关靶点提供了进一步支持。
