PDF(Pubmed)
Abstract：
Schistosomiasis, caused by Schistosoma trematodes, is a significant global health concern, particularly affecting millions in Africa and Southeast Asia. Despite efforts to combat it, the rise of praziquantel (PZQ) resistance underscores the need for new treatment options. Protein kinases (PKs) are vital in cellular signaling and offer potential as drug targets. This study focused on focal adhesion kinase (FAK) as a candidate for anti-schistosomal therapy. Transcriptomic and proteomic analyses of adult S. mekongi worms identified FAK as a promising target due to its upregulation and essential role in cellular processes. Molecular docking simulations assessed the binding energy of FAK inhibitors to Schistosoma FAK versus human FAK. FAK inhibitor 14 and PF-03814735 exhibited strong binding to Schistosoma FAK with minimal binding for human FAK. In vitro assays confirmed significant anti-parasitic activity against S. mekongi, S. mansoni, and S. japonicum, comparable to PZQ, with low toxicity in human cells, indicating potential safety. These findings highlight FAK as a promising target for novel anti-schistosomal therapies. However, further research, including in vivo studies, is necessary to validate efficacy and safety before clinical use. This study offers a hopeful strategy to combat schistosomiasis and reduce its global impact.
摘要：
血吸虫病,由血吸虫引起，是一个重大的全球健康问题，尤其影响着非洲和东南亚的数百万人。尽管努力打击它，吡喹酮（PZQ）耐药性的上升强调了对新治疗方案的需求。蛋白激酶（PKs）在细胞信号传导中至关重要，并具有作为药物靶标的潜力。这项研究的重点是粘着斑激酶（FAK）作为抗血吸虫治疗的候选药物。成虫S.mekongi蠕虫的转录组学和蛋白质组学分析将FAK确定为有希望的靶标，因为它在细胞过程中具有上调和重要作用。分子对接模拟评估了FAK抑制剂对血吸虫FAK与人FAK的结合能。FAK抑制剂14和PF-03814735表现出与血吸虫FAK的强结合,而与人FAK的结合最小。体外试验证实了对S.mekongi的显着抗寄生虫活性，S.Mansoni,和日本血吸虫,与PZQ相比，在人类细胞中具有低毒性，表明潜在的安全。这些发现强调了FAK作为新型抗血吸虫疗法的有希望的靶标。然而,进一步研究,包括体内研究，在临床使用前验证疗效和安全性是必要的。这项研究为抗击血吸虫病和减少其全球影响提供了一个有希望的策略。
