Novel Antimalarials from Marine Microbial Natural Products

来自海洋微生物天然产物的新型抗疟药

基本信息

批准号：
8302637
负责人：
DEBOPAM CHAKRABARTI
金额：
$ 22.84万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302637
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

项目摘要

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" PUBLIC HEALTH RELEVANCE: Malaria is one of the major tropical diseases afflicting over 300 million and killing about 1 million individuals annually. Majority of the current treatments fo malaria are becoming ineffective because of emergence of drug resistance parasites. Therefore, it is urgent to develop new malaria therapeutics to mitigate this serious problem. 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 intervention for the disease.

描述（由申请人提供）：全世界每年有超过 3 亿例疟疾临床病例，导致超过 100 万人死亡，主要是 5 岁以下儿童。世界上超过 41% 的人口生活在疟疾传播地区。疟疾造成的全球经济损失是惊人的。除了严重影响最贫穷国家的儿童总体死亡率外，该疾病估计还会导致疟疾负担较重的国家的经济增长下降约 1.3%。不幸的是，目前用于疟疾治疗的大多数药物都是 30 多年前开发的，其中许多是旧药物的衍生物。由于缺乏大规模努力开发抗疟疾新药，大多数抗疟药由于广泛的耐药性而变得无效。用于发现治疗疟疾的新疗法的投资很少，引入市场的新疗法的数量也相应较少。考虑到全球疟疾造成的死亡人数和耐药性的蔓延，确定可开发成治疗耐药性疟疾的疗法的新化学实体非常重要。拟议的研究项目旨在从海洋微生物中及时发现针对疟疾寄生虫的新型化学实体，并将为该疾病的新型治疗干预措施提供切入点。我们的方法是利用港口分院海洋研究所海洋微生物培养物保藏中心 (HBMMCC) 的化学和生物多样性作为新型生物活性天然产品的来源。我们将使用 SYBR Green I 荧光测定来测定新型海洋微生物提取物文库抑制疟疾寄生虫生长的能力。将使用液相色谱-质谱 (LC-MS) 和 NMR 方法对活性提取物进行去复制，并且将进一步分析那些具有最大新型化学潜力的提取物对一组耐药恶性疟原虫菌株的活性，以确定其效力，以及哺乳动物细胞系有助于评估治疗指数。将通过生物测定引导的分馏来提取具有强抗疟原虫效力、对哺乳动物细胞低毒性和新颖化学成分的提取物，以鉴定生物活性成分的结构。拟议的研究意义重大，因为在该项目结束时，我们预计将获得一系列抗疟“热门药物” 公共卫生相关性：疟疾是主要热带疾病之一，每年影响 3 亿多人，并导致约 100 万人死亡。由于耐药寄生虫的出现，目前大多数疟疾治疗方法都变得无效。因此，迫切需要开发新的疟疾疗法来缓解这一严重问题。拟议的研究项目旨在从海洋微生物中及时发现针对疟疾寄生虫的新型化学实体，并将为该疾病的新型治疗干预提供切入点。