The diterpenoid 7-keto-sempervirol, derived from Lycium chinense, displays anthelmintic activity against both Schistosoma mansoni and Fasciola hepatica.
The diterpenoid 7-keto-sempervirol, derived from Lycium chinense, displays anthelmintic activity against both Schistosoma mansoni and Fasciola hepatica.
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DOI：
10.1371/journal.pntd.0003604
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发表时间：
2015-03
影响因子：
3.8
通讯作者：
Hoffmann KF
中科院分区：
文献类型：
--
作者：
Edwards J;Brown M;Peak E;Bartholomew B;Nash RJ;Hoffmann KF
具有生物医学和商业意义的两种扁形动物是曼氏血吸虫（血吸虫）和肝片吸虫（肝吸虫）。这些相关的吸虫是负责慢性被忽视的热带疾病血吸虫病和片形吸虫病，分别。由于目前没有疫苗可用于抗杀吸虫免疫预防，目前的治疗是通过单一化学化疗介导的，其形式是大规模药物给药（MDA）（吡喹酮用于血吸虫病）或灌服（三氯苯达唑用于片形吸虫病）方案。这种对单一化疗类别的过度依赖极大地限制了进入驱虫药物发现管道的新型化学实体的数量，对可持续的血液和肝吸虫控制的未来提出了重大关切。本文证明了从枸杞中分离得到的二萜类化合物7-酮-森匹韦醇具有双重驱虫活性。mansoni和F.肝吸虫使用基于微量滴定板的蠕虫荧光生物测定法（HFB），该活性对S具有特异性（与HepG 2细胞系相比，治疗指数= 4.2）和中等效力（LD 50 = 19.1 μM）。曼氏童虫体外培养。这种抗童虫作用转化为对体外培养的成年雄性和雌性童虫的活性，其中7-酮-森匹韦罗对运动性/行为、表面结构（诱导皮层孔、结节肿胀和棘缺失/缩短）、产卵率和卵形态产生负面影响。如通过HFB和显微镜表型评分矩阵所评估的，7-酮-森匹韦罗也有效地杀死体外培养的F。肝吸虫新脱囊幼体（NEJs，LD 50 = 17.7 μM）。扫描电子显微镜（SEM）评价成F。在体外与7-酮-森匹韦罗共培养的肝吸虫还显示出表型异常，包括表皮完整性的破坏和棘缺失。7-酮-赛泼韦罗对引起重大人类和动物传染病的两种相关致病性吸虫的活力和表型有负面影响。这种植物衍生的天然产品也对幼虫和成虫发育形式具有活性。因此，这些数据共同表明7-酮-森匹韦罗是驱虫药物开发的重要起点。药物化学优化更有效的7-酮-sempervirol类似物可能导致识别新的化学实体，用于未来的组合或替代驱虫控制。血吸虫病和片形吸虫病是由扁形动物门内发现的两种相关吸虫引起的，由于它们对生活在世界上最贫困地区的人们的影响，被列为被忽视的贫困疾病。由于目前没有疫苗接近开发，并且现有的全球控制策略基于对单一类别化疗的过度依赖，因此迫切需要鉴定下一代驱虫剂。在这里，我们表明，7-酮-sempervirol，来自枸杞的天然产物，显示双重驱虫活性对曼氏血吸虫（血吸虫病的病原体）和肝片吸虫（肝片吸虫病的病原体）。利用客观和表型矩阵，我们表明这种活性是选择性的（与人细胞系相比），对S。mansoni和F.肝幼虫这种抗幼虫作用转化为对S. mansoni和F. 7-酮-森匹韦罗诱导表型异常，包括表皮损伤、运动性破坏和产卵抑制。由于7-酮-sempervirol对两种寄生吸虫的多个生命阶段的驱虫活性，我们认为这种起始化学支架可用于开发更有效的化合物，用于控制生物医学和商业相关的重要寄生虫。
Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control. Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. 7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control. Schistosomiasis and fascioliasis are caused by two related trematodes found within the phylum Platyhelminthes (flatworms), and are classified as neglected diseases of poverty due to their effects on people living in the most underprivileged areas of the world. With no vaccine currently near development, and the existing strategy for global control based on the over-reliance on single-class chemotherapies, there is an urgent requirement for the identification of next generation anthelmintics. Here we demonstrate that 7-keto-sempervirol, a natural product derived from Lycium chinense, displays dual anthelmintic activity towards both Schistosoma mansoni (causative agent of schistosomiasis) and Fasciola hepatica (causative agent of fascioliasis). Utilising objective and phenotypic matrices, we show this activity to be selective (compared to a human cell line) and moderately potent against S. mansoni and F. hepatica larvae. This anti-larval effect translates into additional activity against both S. mansoni and F. hepatica adults where 7-keto-sempervirol induces phenotypic abnormalities including tegumental damage, motility disruption and oviposition inhibition. Due to 7-keto-sempervirol’s anthelmintic activity against multiple life stages of two parasitic trematodes, we contend that this starting chemical scaffold could be used to develop more effective compounds useful in controlling important parasites of biomedical and commercial relevance.
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