Discovery and Mechanism of Antimalarial Natural Products

抗疟天然产物的发现及其作用机制

基本信息

批准号：
9272837
负责人：
Maria Belen Cassera
金额：
$ 39.41万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
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/9272837
关键词：
Africa South of the Sahara Antimalarials Artemisinins Biochemical Biological Biological Assay 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 Institutes Investigation Lead Libraries Literature Liver Malaria Mammalian Cell Medical Medical History Metabolic Molecular Molecular Target Natural Products Natural Resources Parasitic Diseases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phenotype Plant Extracts Plant Taxonomy Plants Plasmodium falciparum Proteomics Quinine Recording of previous events Research Resistance Sampling Selection Criteria Series Source Specimen Structure Structure-Activity Relationship Synthesis Chemistry Therapeutic Intervention Toxic effect Virginia Work analog asexual base biological systems cytotoxicity drug candidate drug development drug testing improved indexing inhibitor/antagonist metabolomics novel novel therapeutics programs public health relevance repository resistant strain response screening transcriptomics

项目摘要

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（由申请人提供）：疟疾和其他寄生虫病是发展中国家目前面临的最严重的健康问题，而恶性疟疾是撒哈拉以南非洲地区尤其严重的问题。药物开发是减少疟疾对全球影响的必要方法，因为这是使目前患有这种疾病的数百万人受益的唯一方法。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也用于治疗疟疾。然而，由于缺乏对其作用机制的了解，新的抗疟天然产品的开发受到阻碍。这项研究将在一个合作项目中将弗吉尼亚理工大学 (VT) 两个研究小组的抗疟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，以挖掘天然产品作为抗疟药物的巨大潜力。 NPDI 拥有超过 22,000 个样本的存储库，这些样本由总共约 7500 个植物标本制备而成。该系列中 12 种具有用作抗疟药物的民族病史的植物的一组提取物的抗疟活性已在 VT 得到验证，这些提取物将由 NPDI 提供，用于从用于补充和治疗的植物中分离新型抗疟化合物。替代医学（CAM）。此外，VT 的 Belen Cassera 博士将使用标准抗疟生物测定法对 NPDI 的所有 22,000 种提取物进行抗疟活性分析，以鉴定活性提取物。通过严格选择标准的提取物将由 VT 的 David Kingston 博士进行分级，他将从民族医学提取物和通过筛选整个 NPDI 收集而发现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阶段特异性活性（无性红细胞内阶段、杀配子细胞阶段和肝脏阶段）以及杀细胞和抗顶质体活性，以鉴定具有不同作用模式的先导抑制剂。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其作用模式和潜在的分子靶标，最终目标是寻找具有新作用机制的新型抗疟药物。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。