In vitro and in vivo activities of DW-3-15, a commercial praziquantel derivative, against Schistosoma japonicum
In vitro and in vivo activities of DW-3-15, a commercial praziquantel derivative, against Schistosoma japonicum
复制标题
商业吡喹酮衍生物 DW-3-15 抗日本血吸虫的体外和体内活性
DOI：
10.1186/s13071-019-3442-7
复制
发表时间：
2019-05
影响因子：
3.2
通讯作者：
Xia Chaoming
中科院分区：
文献类型：
--
作者：
Wang Xiaoli;Yu Dan;Li Chunxiang;Zhan Tingzheng;Zhang Tingting;Ma Huihui;Xu Jing;Xia Chaoming
背景：血吸虫病是一种使人衰弱、被忽视的热带疾病，影响着全世界约 1.9 亿人。吡喹酮 (PZQ) 是唯一可用于对抗所有血吸虫属的药物。尽管 PZQ 具有很高的疗效，但公认的担忧促使开发新的替代药物，以便在 PZQ 对血吸虫菌株的功效降低的流行地区重复使用。在单个分子内包含不同药效团的混合药物是一种有前途的策略。我们早期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着的抗寄生虫活性。本研究中，制药公司大量合成了DW-3-15，其杀血吸虫功效和稳定性得到进一步证实。在体外评估了寄生虫活力、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，还检测了日本血吸虫皮膜的形态变化。结果：体外研究表明DW-3-15对日本血吸虫具有抗寄生虫活性，显着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 在雄性蠕虫中诱导了类似的超微结构变化和明显的外皮表面破坏。在体内，小鼠连续五天每天口服 400 mg/kg 剂量的 DW-3-15 显着降低了肝脏中的总蠕虫负荷和虫卵数量。肝脏的组织学分析显示卵肉芽肿的平均直径显着减小。结论：我们的研究结果表明，DW-3-15是一种具有商业化生产前景的PZQ衍生物，可以开发为一种潜在的血吸虫药。
Background: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.Results: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.Conclusions:Our findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide.
登录
查看更多内容
影响因子：
2.7
作者：
Dong, Yuxiang;Chollet, Jacques;Vennerstrom, Jonathan L.
通讯作者：
Vennerstrom, Jonathan L.
具有吡喹酮耐药性的血吸虫病模型
影响因子：
1.4
作者：
Qi, Longxing;Cui, Jing-an
通讯作者：
Cui, Jing-an
DOI：
10.1016/s1473-3099(10)70169-9
发表时间：
2010-09
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
J. Utzinger;M. Tanner;J. Keiser
通讯作者：
J. Utzinger;M. Tanner;J. Keiser
DOI：
10.1016/s1473-3099(16)30475-3
发表时间：
2017-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Mutapi F;Maizels R;Fenwick A;Woolhouse M
通讯作者：
Woolhouse M
影响因子：
4
作者：
Pica-Mattoccia, L;Cioli, D
通讯作者：
Cioli, D