Discovery and Mechanism of Antimalarial Natural Products

描述（由申请人提供）：疟疾和其他寄生虫病是目前发展中国家面临的最大健康问题，恶性疟原虫疟疾是撒哈拉以南非洲特别严重的问题。药物开发是减少疟疾在世界范围内影响的必要办法，因为这是唯一能使目前患有这种疾病的数百万人受益的办法。天然产物是已知的抗疟化合物的极好来源。两种最有效的抗疟药物（奎宁和青蒿素）是天然产物，许多合成抗疟药物是这两种天然产物的类似物。除了使用分离的天然产物作为抗疟剂外，许多植物在民族医学上用于治疗疟疾。然而，由于缺乏对其作用机制的了解，新的抗疟天然产物的开发受到阻碍。这项研究将把弗吉尼亚理工大学（VT）两个研究小组的抗疟疾专业知识与天然产物发现研究所（NPDI）的天然产物资源结合在一个合作项目中，以挖掘天然产物作为抗疟剂的巨大潜力。国家植物研究所保存了一个从总共约7500个植物标本中提取的超过22,000个样品的储存库。从本收集的12种植物中提取的一组提取物的抗疟活性已在VT上得到验证，这些提取物将由NPDI提供，用于从补充和替代医学（CAM）中使用的植物中分离出新的抗疟化合物。此外，来自NPDI的所有22,000种提取物将由VT的Belen Cassera博士使用标准的抗疟疾生物测定法检测抗疟疾活性，以确定活性提取物。通过严格筛选标准的提取物将由VT的David Kingston博士进行分馏，他将从民族医学提取物和通过筛选整个NPDI收集的活性提取物中分离并确定活性化合物的结构。将评估分离化合物的分期特异性活性（无性红细胞期、杀配子体期和肝期），以及杀细胞和抗顶质体活性，以确定不同作用模式的先导抑制剂。然后将选择三个最有希望的线索，利用蛋白质组学、代谢组学和转录组学方法阐明它们的作用模式和潜在的分子靶点，最终目标是找到一种具有新的作用机制的新型抗疟药。合成化学将为未来的药物开发提供这些先导化合物的类似物。

DESCRIPTION (provided by applicant): Malaria and other parasitic diseases are the greatest health problem currently facing the developing world, and P. falciparum malaria is a particularly severe problem in sub-Saharan Africa. Drug development is a necessary approach to reducing the worldwide impact of malaria, because it is the only approach that will benefit the millions of people currently afflicted with this disease. Natural products are a known, excellent source of antimalarial compounds. Two of the most effective antimalarial drugs (quinine and artemisinin) are natural products, and many synthetic antimalarial drugs are analogs of these two natural products. In addition to the use of isolated natural products as antimalarial agents, many plants are used ethno medically for the treatment of malaria. The development of new antimalarial natural products is however handicapped by a lack of understanding of their mechanism of action. This research will combine the antimalarial expertise of two research groups at Virginia Tech (VT) with the natural product resources of the Natural Products Discovery Institute (NPDI) in a collaborative program to tap into the enormous potential of natural products to serve as antimalarial agents. The NPDI maintains a repository of over 22,000 samples prepared from a total of approximately 7500 plant specimens. The antimalarial activity of a set of extracts from twelve plants in this collection with an ethno medical history of use as antimalarial agents has been validated at VT, and these extracts will be supplied by NPDI for isolation of novel antimalarial compounds from plants used in complementary and alternative medicine (CAM). In addition, all 22,000 extracts from the NPDI will be assayed for antimalarial activity by Dr. Belen Cassera at VT using a standard antimalarial bioassay to identify active extracts. Extracts which pass rigorous selection criteria will then be fractionated by Dr. David Kingston at VT, who will isolate and determine the structures of the active compounds from both the ethno medical extracts and active extracts found by screening the entire NPDI collection. Isolated compounds will be evaluated for stage specific activity (asexual intraerythrocytic stages, gametocytocidal, and liver stages), as well as cytocidal and anti-apicoplast activity to identify lead inhibitors wih different modes of action. The three most promising leads will then be selected to elucidate their mode of action and potential molecular target(s) using proteomics, metabolomics and transcriptomics approaches, with the ultimate goal of finding a novel antimalarial agent with a new mechanism of action. Synthetic chemistry will provide analogs of these lead compounds for future drug development.