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枸杞子活性成分衍生两种危及生命疾病的潜在新药

已有 684 次阅读 2018-7-11 09:49 |个人分类:饮食与健康|系统分类:论文交流| 枸杞子, 活性成分, 血吸虫病, 肝片吸虫病, 潜在新药

枸杞子活性成分衍生两种危及生命疾病的潜在新药

诸平

据英国卡迪夫大学( Cardiff University2018年7月5日提供的消息,该大学的安德鲁·韦斯特维尔教授(Professor Andrew Westwell)领导的研究团队,受到枸杞子浆果(Lycium chinense, goji berry)中已成功地提取出了一种对血吸虫(Schistosoma mansoni)和肝片吸虫(Fasciola hepatica)有灭杀活性化合物(diterpenoid 7-keto-sempervirol (Fig. 1C)的启发,成功地合成出结构类似的化合物30种。对其进行药效试验,筛选出药效良好的一种(7d),有望成为血吸虫(Schistosoma mansoni)和肝片吸虫(Fasciola hepatica)这2种危及生命疾病的潜在新药。

对引起血吸虫病(schistosomiasis)和肝片吸虫病(fascioliasis)的寄生虫起作用。尽管不太为人所知,血吸虫病是仅次于疟疾的最具破坏性的一种人类寄生虫病,目前约有6亿人受到血吸虫并得困扰和影响,每年约有30万人因为血吸虫病而死亡。同样,目前有1700万人感染了肝片吸虫病,而且这些数字还会增加。

血吸虫病是由水传播的寄生虫而引起的,而肝片吸虫病则是由食源性寄生虫(foodborne parasite)引起的。这两种被忽视的疾病都是用一种药物治疗的,这种药物在这些疾病最流行的人群中得到了广泛的应用。然而,这种单一的治疗往往会导致耐药性,现在许多人都面临感染这些疾病的风险。

卡迪夫大学(Cardiff University)的一组研究人员与阿伯里斯特威斯大学的生物科学、环境科学和乡村科学研究所(Aberystwyth University’s Institute of Biological, Environmental and Rural Sciences)合作,由卡尔·霍夫曼教授(Professor Karl Hoffmann)领导,合作研究发现了一种新的药物治疗方法。

来自卡迪夫大学药学院(Cardiff University’s School of Pharmacy and Pharmaceutical Sciences)安德鲁·韦斯特维尔教授说:“发现一种潜在的新的治疗两种如此普遍疾病的药物,是一个令人兴奋的发现,我们希望这项研究将惠及世界上受到血吸虫病和肝片吸虫病困扰更多人群。

此项研究是由威尔士政府的威尔士生命科学研究网(Welsh Government’s Life Science Research Network of Wales)提供资助的,药物设计是由卡迪夫大学药学院完成的,而药效实验是由阿伯里斯特威斯大学(Aberystwyth University)进行的。此研究成果已经在《欧洲医学化学杂志》(European Journal of Medical Chemistry)上发表——Crusco A, Bordoni C, Chakroborty A, Whatley KCL, Whiteland H, Westwell A D, Hoffmann K F. Design, synthesis and anthelmintic activity of 7-keto-sempervirol analogues. Eur J Med Chem, 2018 May 25; 152: 87-100. doi: 10.1016/j.ejmech.2018.04.032.点击可以免费直接浏览原文

Highlights

  •  30 analogues of the anthelmintic diterpenoid 7-keto-sempervirol were synthesised.

  • Analogues were screened against S. mansoni and F. hepatica juvenile and adult stages.

  • Compound 7d showed improved dual anthelmintic activity over 7-keto-sempervirol.

  • Compound 7d inhibited egg production and affected surface tegument integrity.

 

 Abstract

The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC50 = 19.1 μM) and Fasciola hepatica (IC50 = 17.7 μM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto-sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto-sempervirol (IC50 ≈ 6 μM for larval blood flukes; IC50 ≈ 3 μM for juvenile liver flukes) and moderate selectivity (SI ≈ 4–5 for blood flukes, 8–13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad-spectrum anthelmintic.

Graphical abstract

Image 1



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