云南抗血吸虫抗疟活性植物与有效成分基础研究

Schistosomiasis and malaria are serious diseases seriously harmful to people's health. Although a few drugs like praziquantel and artemisinin can currently be used all over the world to control the diseases, however, these medicines have significant defects such as severe side effects and the molecular structural similarity which can lead to great risk that all the drugs may lose the anti-parasite effects together due to parasite drug-resistance increasing. Therefore, to develop new generation of anti-parasite drugs as the complementary and alternative drugs is of great significance for the strategic security to prevent and control the parasite diseases. According to the rules for drug development, it is definitively an important way to start researches from natural products. Yunnan is rich in medicinal plant resources. By systematical integration and screens, it is quite possible to find potential candidates or lead compounds for new generation of anti-parasite drugs from Yunnan plant resources. Based on such conception, this project plans to collect more than 400 different plant samples from most plant families distributed in Yunnan. By in vitro assays, anti-schistosomal and anti-malarial activities of the samples will be evaluated, and 8-10 plant samples which show strong bioactivities will be selected for further study to determine the major bioactive constituents. 1-2 compounds which have best activities in the in vitro assays and low cute toxicity will be subjected to animal study to evaluate the in vivo anti-schistosomal and anti-malarial activities. Moreover, the structure-active relationship will be studied as well by synthetic chemistry and in vitro bioactive assays. The purpose of this study is to lay research foundations for the development of new generation of anti-schistosomal and anti-malarial drug in the future.

血吸虫病、疟疾等是严重危害人类健康的疾病，目前全球虽有吡喹酮、青蒿素等少数几个药物可以控制，但这些药物结构单一、副作用明显，同时有因虫体耐药性增加而集体失效的风险，因此寻找替代性药物、加快新一代抗血吸虫抗疟药物研究、确保寄生虫病防治药物战略安全，意义重大。根据药物研发规律，由天然产物中寻找活性成分或先导化合物是一个重要的发现新一代抗血吸虫、抗疟药物的手段。云南药用植物资源异常丰富，如能通过系统的整合筛选，很有可能从中发现具有研究、开发潜力的新一代抗血吸虫、抗疟药物。本项目拟先以体外活性筛查的方式，对400种以上产自云南不同生长环境、不同科属的植物样品进行抗血吸虫、抗疟活性初步测试，确定8-10种效果较好的植物样品，进行活性成分跟踪分离、结构鉴定；继而选取1-2种有潜力的成分以动物实验方式进行活性效果评价，并进行适当的结构改造，了解构效关系，为研发新一代抗血吸虫、抗疟药物提供基础性研究依据。

疟疾、血吸虫病等是严重危害人类健康的寄生虫病，目前全球虽有青蒿素、吡喹酮等少数几个药物可以控制，但存在着因虫体耐药性增加而集体失效的风险，加快新一代抗疟抗血吸虫药物研究、确保寄生虫病防治药物战略安全意义重大。云南植物资源异常丰富，具有研发新一代抗疟抗血吸虫药物巨大潜力。为此，本项目先后对105科302属390种植物衍生出的882个供试样品进行了体外β-羟高铁血红素形成抑制活性测试抗疟活性筛选；对其中活性较好的8种植物进行了活性成分研究，分离鉴定了一系列具有较好β-羟高铁血红素形成抑制活性的化学成分，并发现了酚性成分与β-羟高铁血红素形成抑制活性之间存在着明显的构效关系，由此对该体外抗疟检测方法的可靠性提出了疑问。为此，本项目专门建立了约氏疟原虫鼠疟抗疟活性筛选方法，并对382种植物样品粗提物进行了动物模型抗疟活性筛选，发现了28种植物具有良好的抗疟活性，实验结果与上述体外抗疟活性结果并不吻合，显示体外抗疟方法存在着活性样品偏筛漏筛的缺陷，为今后抗疟方法可靠性研究与实际应用提供了实验依据。项目还对动物模型抗疟活性最好的植物样品进行了活性成分与构效关系初步研究，分离鉴定了一系列萜类活性成分，其中以二降萜类化合物活性最好。药理作用机制初步研究结果显示，该二降萜类成分可对宿主免疫功能产生影响，有助于宿主免疫力提升，并可显著影响疟原虫线粒体膜电位。本项目还创建了一种全新的体外抗血吸虫活性筛选方法，并对20种植物样品进行了体外抗血吸虫活性测试。本项目已发表相关研究论文11篇，接受待发表论文4篇；申请专利6项，培养硕士研究生11人。相关研究工作为抗寄生虫药物研究提供了一个全新的视角，为由云南丰富的植物资源中研发新型抗疟抗血吸虫药物奠定了基础，为国家抗寄生虫药物战略安全提供了新的实验依据，因此具有十分重要的科学意义与良好的应用前景。