Novel Antimalarials from Marine Microbial Natural Products

来自海洋微生物天然产物的新型抗疟药

• 批准号: 8424201
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 18.09万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424201
• 关键词: Antimalarials; Area; Biodiversity; Biological Assay; Biological Factors; Cell Line; Cessation of life; Chemicals; Chemistry; Child; Childhood; Clinical; Collection; Country; Data; Development; Disease; Dose; Drug resistance; Economics; Ecosystem; Evaluation; Exhibits; Florida; Fluorescence; Fractionation; Goals; Growth; Individual; Institutes; Investments; Laboratory Research; Lead; Libraries; Malaria; Mammalian Cell; Marine Invertebrates; Marines; Marketing; Methodology; Methods; Microbe; Microbiology; Molecular; Natural Products Chemistry; Nuclear Magnetic Resonance; Parasites; Pharmaceutical Preparations; Plants; Plasmodium falciparum; Population; Porifera; Production; Rain; Research; Research Project Grants; SYBR Green I; Source; Structure; Taxon; Testing; Therapeutic; Therapeutic Index; Toxic effect; Tropical Disease; Universities; Ursidae Family; base; cytotoxicity; experience; forest; interest; killings; liquid chromatography mass spectrometry; liquid chromatography mass spectroscopy; marine natural product; member; microbial; microorganism; mortality; next generation; novel; novel therapeutic intervention; novel therapeutics; response; scaffold; scale up

DESCRIPTION (provided by applicant): There are over 300 million clinical episodes of malaria each year worldwide with over 1 million deaths, primarily in children under 5. Over 41% of the world's population lives in areas where malaria is transmitted. The global economic toll of malaria is staggering. In addition to contributing significantly towards overall childhood mortalit in the poorest nations, the disease is estimated to cause approximately a 1.3% reduction in economic growth in countries that bear a heavy malaria burden. Unfortunately, most of the drugs that are currently being used for malaria treatment were developed more than 30 years ago and many are derivatives of older drugs. In the absence of a large-scale effort to develop novel drugs against malaria, most antimalarials have now become ineffective due to widespread drug resistance. Investment in the discovery of new therapeutics for the treatment of malaria has been sparse and the number of new treatments introduced to the market is correspondingly low. Given the global toll of malaria and the spread of drug resistance, it is important to identif new chemical entities that can be developed into therapeutics for the treatment of drug-resistant malaria. The proposed research project seeks to discover novel chemical entities from marine microbes targeting the malaria parasite is timely and will provide entry into novel therapeutic interventions for the disease. Our approach will be to tap into the chemical and biological diversity of the Harbor Branch Oceanographic Institute Marine Microbial Culture Collection (HBMMCC) as a source of novel bioactive natural products. We will assay a novel library of marine microbe derived extracts for their ability to inhibit the growth of the malaria parasite usig the SYBR Green I Fluorescent assay. Active extracts will be dereplicated using Liquid-chromatography- mass spectroscopy (LC-MS) and NMR methodologies and those with the greatest potential for novel chemistry will be further profiled for their activity against a panel f drug resistant Plasmodium falciparum strains to define potency, and the mammalian cell lines to help assess therapeutic index. Extracts with strong potency against the malaria parasite, low toxicity to mammalian cells and novel chemistry will be taken through bioassay- guided fractionation to identify the structure of bioactive components. The proposed research is significant because at the end of this project we expect to have a portfolio of antimalarial "hits"

描述(申请人提供)：全世界每年有超过3亿的疟疾临床病例，有100多万人死亡，主要是5岁以下的儿童。世界上超过41%的人口生活在疟疾传播的地区。疟疾造成的全球经济损失令人震惊。除了对最贫穷国家的儿童总死亡率有很大贡献外，据估计，这种疾病还会导致疟疾负担沉重的国家的经济增长减少约1.3%。不幸的是，目前用于治疗疟疾的大多数药物都是在30多年前开发的，其中许多是旧药物的衍生品。在没有大规模努力开发抗疟疾新药的情况下，由于广泛的耐药性，大多数抗疟疾药物现在已经变得无效。在发现治疗疟疾的新疗法方面的投资一直很少，市场上引进的新疗法的数量也相应较少。鉴于全球疟疾造成的死亡和抗药性的蔓延，重要的是确定可发展为治疗抗药性疟疾的治疗药物的新化学物质。拟议的研究项目寻求从海洋微生物中发现针对疟疾寄生虫的新化学实体，这是及时的，并将为该疾病提供新的治疗干预措施。我们的方法将是利用海港分部海洋研究所海洋微生物培养库(HBMMCC)的化学和生物多样性，作为新的生物活性天然产品的来源。我们将测试一个新的海洋微生物提取物文库的能力，以抑制疟疾寄生虫的生长，SYBR Green I荧光试验。活性提取物将使用液-质联用(LC-MS)和核磁共振方法进行分离，那些具有最大潜力进行新化学研究的提取物将进一步分析其对抗药性恶性疟原虫菌株的活性，以确定其效力，并帮助评估哺乳动物细胞系的治疗指数。具有对疟疾寄生虫的强大效力、对哺乳动物细胞的低毒性和新的化学成分的提取物将通过生物测定引导的分离来鉴定生物活性成分的结构。这项拟议的研究具有重要意义，因为在这个项目结束时，我们预计会有一个抗疟疾“热门”组合。