Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226.
Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2217732120. doi: 10.1073/pnas.2217732120. Epub 2022 Dec 27.
The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified- a transient receptor potential ion channel in the melastatin subfamily (TRPM)-however, little is known about the properties of TRPM in other parasitic flatworms. Here, TRPM orthologs were scrutinized from all currently available parasitic flatworm genomes. TRPM is present in all parasitic flatworms, and the consensus PZQ binding site was well conserved. Functional profiling of trematode, cestode, and a free-living flatworm TRPM ortholog revealed differing sensitives (~300-fold) of these TRPM channels toward PZQ, which matched the varied sensitivities of these different flatworms to PZQ. Three loci of variation were defined across the parasitic flatworm TRPM pocketome with the identity of an acidic residue in the TRP domain acting as a gatekeeper residue impacting PZQ residency within the TRPM ligand binding pocket. In trematodes and cyclophyllidean cestodes, which display high sensitivity to PZQ, this TRP domain residue is an aspartic acid which is permissive for potent activation by PZQ. However, the presence of a glutamic acid residue found in other parasitic and free-living flatworm TRPM was associated with lower sensitivity to PZQ. The definition of these different binding pocket architectures explains why PZQ shows high therapeutic effectiveness against specific fluke and tapeworm infections and will help the development of better tailored therapies toward other parasitic infections of humans, livestock, and fish.
吡喹酮（PZQ）是治疗血吸虫病和其他寄生虫扁形动物感染的关键临床疗法。最近发现吡喹酮的一个血吸虫靶标是瞬时受体电位离子通道亚家族成员（TRPM），然而，对于其他寄生虫扁形动物中的 TRPM 特性知之甚少。在这里，从所有现有的寄生虫扁形动物基因组中仔细研究了 TRPM 同源物。TRPM 存在于所有寄生虫扁形动物中，并且 PZQ 结合位点的共识得到了很好的保守。吸虫、绦虫和自由生活扁形动物 TRPM 同源物的功能分析显示，这些 TRPM 通道对 PZQ 的敏感性差异很大（约 300 倍），这与这些不同的扁形动物对 PZQ 的敏感性差异相匹配。在寄生虫扁形动物 TRPM 口袋组中定义了三个变异位点，TRP 结构域中酸性残基的身份作为门控残基，影响 PZQ 在 TRPM 配体结合口袋中的停留时间。在对 PZQ 高度敏感的吸虫和环头绦虫中，该 TRP 结构域残基是天冬氨酸，允许 PZQ 进行有效激活。然而，在其他寄生虫和自由生活扁形动物 TRPM 中发现的谷氨酸残基的存在与对 PZQ 的敏感性降低有关。这些不同结合口袋结构的定义解释了为什么 PZQ 对特定的吸虫和绦虫感染具有高治疗效果，并将有助于针对人类、牲畜和鱼类的其他寄生虫感染开发更好的靶向治疗方法。
