Schistosomiasis chemotherapy is largely based on praziquantel (PZQ). Although PZQ is very safe and tolerable, it does not prevent reinfection and emerging resistance is a primary concern. Recent studies have shown that the targeting of epigenetic machinery in Schistosoma mansoni may result in severe alterations in parasite development, leading to death. This new route for drug discovery in schistosomiasis has focused on classes of histone deacetylases (HDACs) and histone acetyltransferases (HATs) as epigenetic drug targets. Schistosoma histone demethylases also seem to be important in the transition of cercariae into schistosomula, as well as sexual differentiation in adult worms. The Target-Pathogen database and molecular docking assays were used to prioritize the druggability of S. mansoni histone demethylases. The transcription profile of Smp_03400 was re-analyzed using available databases. The effect of GSK-J4 inhibitor in schistosomula and adult worms’ motility/viability/oviposition was assessed by in vitro assays. Ultrastructural analysis was performed on adult worms exposed to GSK-J4 by scanning electron microscopy, while internal structures and muscle fiber integrity was investigated by confocal microscopy after Langeronʼs carmine or phalloidin staining. The present evaluation of the potential druggability of 14 annotated S. mansoni demethylase enzymes identified the S. mansoni ortholog of human KDM6A/UTX (Smp_034000) as the most suitable druggable target. In silico analysis and molecular modeling indicated the potential for cofactor displacement by the chemical probe GSK-J4. Our re-analysis of transcriptomic data revealed that Smp_034000 expression peaks at 24 h in newly transformed schistosomula and 5-week-old adult worms. Moreover, this gene was highly expressed in the testes of mature male worms compared to the rest of the parasite body. In in vitro schistosome cultures, treatment with GSK-J4 produced striking effects on schistosomula mortality and adult worm motility and mortality, as well as egg oviposition, in a dose- and time-dependent manner. Unexpectedly, western blot assays did not demonstrate overall modulation of H3K27me3 levels in response to GSK-J4. Confocal and scanning electron microscopy revealed the loss of original features in muscle fibers and alterations in cell-cell contact following GSK-J4 treatment. GSK-J4 presents promising potential for antischistosomal control; however, the underlying mechanisms warrant further investigation.

中文翻译：

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H3K27脱甲基酶抑制剂GSK-J4的抗血吸虫病潜力：分子建模，转录组学和体外测定的见解

血吸虫病化疗主要基于吡喹酮（PZQ）。尽管PZQ非常安全并且可以耐受，但是它不能防止再次感染，因此出现新的耐药性是一个主要问题。最近的研究表明，曼氏血吸虫中表观遗传机制的靶向可能导致寄生虫发育的严重改变，从而导致死亡。这种在血吸虫病中发现药物的新途径集中于组蛋白脱乙酰基酶（HDACs）和组蛋白乙酰基转移酶（HATs）作为表观遗传学药物靶标。血吸虫组蛋白脱甲基酶在尾c向血吸虫的过渡以及成虫的​​性别分化中似乎也很重要。使用Target-Pathogen数据库和分子对接测定法来优先确定曼氏葡萄球菌组蛋白脱甲基酶的可药用性。使用可用的数据库重新分析了Smp_03400的转录谱。通过体外试验评估了GSK-J4抑制剂对血吸虫和成虫的运动/生存能力/产卵的影响。通过扫描电子显微镜对暴露于GSK-J4的成虫进行了超微结构分析，而在兰格隆的胭脂红或鬼笔环肽染色后，通过共聚焦显微镜研究了内部结构和肌肉纤维完整性。目前对14种带注释的曼氏葡萄球菌脱甲基酶的潜在可药性的评估确定了人KDM6A / UTX（Smp_034000）的曼氏葡萄球菌直系同源物是最合适的可药物化靶标。在计算机分析和分子建模中表明，化学探针GSK-J4可能导致辅因子置换。我们对转录组数据的重新分析显示，在新转化的血吸虫和5周龄的成虫中，Smp_034000的表达在24小时达到峰值。而且，与其他寄生虫体相比，该基因在成熟的雄性蠕虫的睾丸中高表达。在体外血吸虫培养物中，用GSK-J4处理对血吸虫的死亡率，成虫的蠕动和死亡率以及卵子的产卵具有明显的剂量和时间依赖性。出乎意料的是，western blot分析未显示出响应GSK-J4的H3K27me3水平的整体调节。共聚焦和扫描电子显微镜显示，在进行GSK-J4处理后，肌肉纤维的原始特征丧失，细胞与细胞之间的接触发生改变。GSK-J4具有抗血吸虫病控制的潜力。然而，