Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA.
Computational Chemistry and Biology, Global Research & Development, Discovery Technologies, Merck Healthcare, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Sci Transl Med. 2021 Dec 22;13(625):eabj5832. doi: 10.1126/scitranslmed.abj5832.
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 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) 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 homologs in other PZQ-sensitive flukes, but not . However, a single amino acid change in the TRPM binding pocket, to mimic schistosome TRPM, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved.
吡喹酮（PZQ）是治疗寄生虫性扁形虫感染（如血吸虫病）的基本药物，全球有超过 2.5 亿人受到感染。然而，PZQ并非对所有寄生虫都有效，它对肝吸虫属的寄生虫没有活性。这种不敏感性的原因尚不清楚，因为 PZQ 的作用机制尚不清楚。在这里，我们使用配体和靶标方法证明，PZQ 通过与通道电压传感器样结构域内的疏水配体结合口袋结合，激活秀丽隐杆线虫中的瞬时受体电位 melastatin 离子通道（TRPM），导致钙内流和蠕虫麻痹。PZQ 激活其他 PZQ 敏感的吸虫中的 TRPM 同源物，但不能激活 。然而，在 TRPM 结合口袋中模拟秀丽隐杆线虫 TRPM 的单个氨基酸变化赋予 PZQ 敏感性。经过几十年的临床应用，PZQ 在可用药靶 TRP 通道中的作用的分子基础得到解决。
