Mechanism of praziquantel action at a parasitic flatworm ion channel.
Mechanism of praziquantel action at a parasitic flatworm ion channel.
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DOI：
10.1126/scitranslmed.abj5832
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发表时间：
2021-12-22
影响因子：
17.1
通讯作者：
Marchant JS
中科院分区：
文献类型：
--
作者：
Park SK;Friedrich L;Yahya NA;Rohr CM;Chulkov EG;Maillard D;Rippmann F;Spangenberg T;Marchant JS
吡喹酮(PZQ)是治疗寄生性扁平线虫感染的基本药物，如血吸虫病，该疾病困扰着2.5亿人。然而，PZQ并不是万能的，缺乏抗片吸虫属肝吸虫的活性。这种不敏感的原因尚不清楚，因为PZQ的作用机制尚不清楚。在这里，我们使用基于配基和靶点的方法来证明PZQ通过在通道的电压传感器样域内结合疏水配体结合口袋来激活血吸虫的瞬时受体电位褪黑素离子通道(TRPMPZQ)，从而导致钙内流和蠕虫瘫痪。PZQ能激活其他对PZQ敏感的吸虫的TRPMPZQ同源物，但不能激活肝片吸虫。然而，模拟血吸虫TRPMPZQ的肝片吸虫TRPMPZQ结合口袋中的单个氨基酸变化赋予了PZQ的敏感性。经过几十年的临床应用，PZQ在可药物色氨酸通道上的作用的分子基础得到了解决。
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.
影响因子：
3.7
作者：
Ahamed M;Chan B;Jensen P;Todd MH
通讯作者：
Todd MH