Department of Parasitology, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China.
Department of Microbiology and Parasitology, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, 2600 Donghai Road, Bengbu, 233030, China.
Parasit Vectors. 2019 May 3;12(1):199. doi: 10.1186/s13071-019-3442-7.
Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. Although PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. A hybrid drug containing different pharmacophores within a single molecule is a promising strategy. Our earlier in vivo studies showed the significant antiparasitic activity of a praziquantel derivative, DW-3-15, against Schistosoma japonicum. In the present study, DW-3-15 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro. An in vivo study was conducted to assess the effect of commercial DW-3-15 on worm burden, egg production and diameter of granulomas. Additionally, to gain insight into the mechanism of action for DW-3-15, morphological changes in the tegument of S. japonicum were also examined.
The in vitro study showed the antiparasitic activity of DW-3-15 against S. japonicum, with significant reductions in viability of adult and juvenile worms, worm pairings and egg output. Compared to PZQ, DW-3-15 induced similar ultrastructural changes and evident destruction of the tegument surface in male worms. In vivo, the oral administration of DW-3-15 at a dose of 400 mg/kg per day for five consecutive days in mice significantly reduced the total worm burden and number of eggs in the liver. Histological analysis of the livers showed a marked reduction in the average diameter of the egg granuloma.
Our findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide.
血吸虫病是一种使人虚弱的被忽视的热带病，影响着全球约 1.9 亿人。吡喹酮（PZQ）是唯一可用于对抗所有血吸虫物种的药物。尽管 PZQ 具有很高的疗效，但人们已经认识到一些问题，因此需要开发新的、可重复使用的替代药物，用于 PZQ 对血吸虫菌株疗效降低的流行地区。将不同药效团结合在单个分子中的杂合药物是一种很有前途的策略。我们之前的体内研究表明，吡喹酮衍生物 DW-3-15 对日本血吸虫具有显著的抗寄生虫活性。在本研究中，一家制药公司大量合成了 DW-3-15，并进一步证实了其杀血吸虫效果和稳定性。我们评估了寄生虫活力、配对和产卵等参数。进行了一项体内研究，以评估商业 DW-3-15 对蠕虫负荷、产卵量和肉芽肿直径的影响。此外，为了深入了解 DW-3-15 的作用机制，还检查了日本血吸虫表皮的形态变化。
体外研究表明，DW-3-15 对日本血吸虫具有抗寄生虫活性，可显著降低成虫和幼虫的活力、成虫配对和产卵量。与 PZQ 相比，DW-3-15 诱导雄性蠕虫产生相似的超微结构变化，并明显破坏表皮表面。在体内，DW-3-15 以 400mg/kg/天的剂量连续口服 5 天，可显著降低小鼠的总蠕虫负荷和肝脏中的虫卵数。肝脏组织学分析显示，虫卵肉芽肿的平均直径明显减小。
我们的研究结果表明，DW-3-15 是一种具有商业生产前景的 PZQ 衍生物，可以开发为一种有前途的杀血吸虫药物。
