QIMR Berghofer Medical Research Institute, Herston, Australia.
School of Medicine, Griffith University, Gold Coast, Australia.
Parasitology. 2020 Nov;147(13):1488-1498. doi: 10.1017/S0031182020001250. Epub 2020 Aug 3.
Praziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47-68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.
吡喹酮（PZQ）是治疗血吸虫病的首选药物。潜在的药物耐药性需要寻找 PZQ 的辅助或替代疗法。先前的功能基因组学研究表明，RNAi 抑制曼氏血吸虫成虫中的钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）基因可显著提高 PZQ 的疗效。在这里，我们测试了 15 种选择性和非选择性 CaMK 抑制剂对曼氏血吸虫的体外疗效，结果表明，当与这些 CaMK 抑制剂联合使用时，PZQ 对耐药性的幼体寄生虫的疗效得到了提高。通过测量 CaMK 活性和曼氏血吸虫成虫的迁移性，我们鉴定出两种非选择性 CaMK 抑制剂，即 Staurosporine（STSP）和 1-萘基 PP1（1NAPP1），它们是进一步研究的有前途的候选药物。我们在感染曼氏血吸虫的小鼠中研究了 STSP 和 1NAPP1 的作用，这些小鼠在存在或不存在亚致死剂量的 PZQ 的情况下，针对 2 天和 7 天龄的尾蚴和成虫进行了治疗。与单独用 PZQ 治疗的小鼠相比，用 STSP/PZQ 治疗可显著（47-68%）降低肝脏虫卵负荷。这些发现表明，与单独使用 PZQ 相比，STSP 和 PZQ 联合用药可显著提高抗血吸虫活性，表明选择性和非选择性 CaMK/激酶抑制剂作为 PZQ 治疗血吸虫病的联合治疗的潜力。
