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目前面临发展中国家的健康问题，而恶性疟原虫疟疾是撒哈拉以南非洲的一个特别严重的问题。药物开发是减少全球疟疾影响的必要方法，因为这是唯一使数百万当前患有这种疾病的人受益的方法。天然产品是抗疟疾化合物的已知，极好的来源。两种最有效的抗疟药（奎宁和青蒿素）是天然产物，许多合成抗疟药是这两种天然产物的类似物。除了将孤立的天然产物用作抗疟药外，许多植物在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，新抗菌天然产物的发展受到了障碍。这项研究将将弗吉尼亚理工大学（VT）两个研究小组的抗疟疾专业知识与自然产品发现研究所（NPDI）的自然产品资源相结合，以利用自然产品的巨大潜力，以充当抗疟药。 NPDI保留了一个由大约7500个植物标本制备的22,000多个样品的存储库。该系列中有十二个植物的一组提取物的抗性活性，其用途是抗菌剂的病史，已在VT上进行了验证，NPDI将提供这些提取物，用于分离从用于互补和替代药物（CAM）中使用的新型抗疟药化合物。此外，使用标准的抗疟疾生物测定法鉴定活性提取物，Belen Cassera博士在VT上将分析NPDI的所有22,000种提取物。然后，通过严格选择标准的提取物将由VT的David Kingston博士分级，后者将通过筛选整个NPDI收集来隔离和确定活性化合物的结构和活性提取物。将评估孤立的化合物的特定阶段活性（无性肢体内阶段，粘粒细胞和肝脏阶段），以及细胞降低和抗副细胞活性，以鉴定铅抑制剂，无论是不同的作用模式。然后，将选择三个最有前途的潜在客户，以使用蛋白质组学，代谢组学和转录组学方法来阐明其作用方式和潜在的分子靶标，其最终目标是找到具有新的作用机理的新型抗疟药。合成化学将为未来的药物开发提供这些铅化合物的类似物。