Discovery and Mechanism of Antimalarial Natural Products

抗疟天然产物的发现及其作用机制

• 批准号: 8627943
• 负责人: Maria Belen Cassera
• 金额: $ 43.66万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627943
• 关键词: Action Potentials; Africa South of the Sahara; Antimalarials; Artemisinins; Biochemical; Biological; Biological Assay; Biological Factors; Chemicals; Chemistry; Chloroquine resistance; Collection; Combined Modality Therapy; Complementary and alternative medicine; Data; Development; Disabled Persons; Disease; Dose; Drug Combinations; Drug resistance; Evaluation; Falciparum Malaria; Fractionation; Future; Goals; Health; Human Cell Line; Inhibitory Concentration 50; Institutes; Investigation; Lead; Libraries; Literature; Liver; Malaria; Mammalian Cell; Medical; Medical History; Metabolic; Molecular; Molecular Target; Parasitic Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Plant Extracts; Plant Taxonomy; Plants; Plasmodium falciparum; Proteomics; Quinine; Recording of previous events; Research; Resistance; Resources; Sampling; Selection Criteria; Series; Source; Specimen; Staging; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Therapeutic Intervention; Toxic effect; Virginia; Work; analog; artemisinine; asexual; base; biological systems; cytotoxicity; drug candidate; drug development; handicapping condition; improved; indexing; inhibitor/antagonist; metabolomics; novel; programs; public health relevance; repository; resistant strain; response; screening; text searching; transcriptomics

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.

描述(申请人提供)：疟疾和其他寄生虫病是发展中国家目前面临的最大健康问题，恶性疟在撒哈拉以南非洲是一个特别严重的问题。药物开发是减少疟疾在世界范围内影响的必要办法，因为这是使目前数百万受疟疾困扰的人受益的唯一办法。天然产品是已知的抗疟疾化合物的极好来源。两种最有效的抗疟疾药物(奎宁和青蒿素)是天然产物，许多合成抗疟疾药物是这两种天然产物的类似物。除了使用单独的天然产品作为抗疟疾药物外，许多植物还被用于治疗疟疾的民族医学。然而，由于缺乏对其作用机制的了解，新的抗疟疾天然产品的开发受到阻碍。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品发现研究所(NPDI)的天然产品资源结合起来，共同开发天然产品作为抗疟疾药物的巨大潜力。NPDI维护着一个超过22,000个样本的储存库，这些样本是从总共大约7500个植物样本中制备出来的。从这个集合中的12种植物中提取的一组提取物的抗疟疾活性已经在VT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疾化合物。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方法进行抗疟疾活性检测，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博士进行分级，他将从民族医药提取物和通过筛选整个NPDI集合发现的活性提取物中分离并确定活性化合物的结构。将对分离的化合物进行阶段特异性活性(无性红细胞内阶段、配子细胞杀灭阶段和肝脏阶段)以及杀细胞和抗质外体活性的评估，以确定具有不同作用模式的铅抑制物。然后将选择三个最有希望的先导化合物，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(S)，最终目标是找到具有新作用机制的新型抗疟疾药物。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。