Discovery of Marine Invertebrate-Derived Antimalarial Agents

海洋无脊椎动物来源的抗疟药物的发现

• 批准号: 8583125
• 负责人: AMY Elizabeth WRIGHT
• 金额: $ 21.81万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583125
• 关键词: Address; Algae; Anopheles Genus; Antimalarials; Area; Artemisinins; Biological; Biological Assay; Biological Factors; Biotechnology; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Child; Clinical; Collaborations; Collection; Combined Modality Therapy; Culicidae; Development; Drug resistance; Falciparum Malaria; Florida; Fractionation; Freezing; Future; Goals; Habitats; Institutes; Invertebrates; Investigation; Investments; Laboratories; Lead; Legal patent; Libraries; Life; Malaria; Marine Invertebrates; Marines; Mass Spectrum Analysis; Methods; Organism; Parasites; Pilot Projects; Plasmodium falciparum; Population; Property; Publishing; Quinine; Reporting; Research; Research Project Grants; Resistance development; Resolution; Resources; Risk; Screening Result; Series; Source; Structure; Therapeutic; Time; Universities; Water; Work; World Health Organization; artemisinine; base; chemical property; disorder prevention; in vivo; marine natural product; novel; novel therapeutic intervention; programs; public health relevance; repository; research study; resistant strain; scaffold; screening; vector transmission

DESCRIPTION (provided by applicant): The CDC estimates that in 2010 over 216 million clinical episodes of malaria occurred worldwide with over 665,000 deaths (with over 86% of deaths being that of children). Over 3.3 billion of the world's populations live in areas where malaria is transmitted and although malaria is not a current threat in the US, the transmission vector for the parasite, Anopheles mosquitoes, is widely prevalent and there remains a constant risk of reintroduction of malaria into the US. Emergence of drug-resistance has been an on-going problem in malaria treatment and even the relatively newly introduced artemisinin-based combination therapies are beginning to develop resistance. Given the global toll of malaria and the continued development of drug resistance, it is important to identify new chemical entities that act via different modes of action and which provide therapeutic options for the treatment of drug-resistant malaria. Natural products have long been an important source of anti-malarial agents with quinine and its synthetic derivatives, artemisinin and its derivatives, all being front line treatments for malaria. Harbor Branch Oceanographic Institute's Marine Biomedical & Biotechnology Research Group (HBOI) has had an on-going marine natural products research program since 1984 and has published reports on over 150 novel bioactive compounds and greater than 100 patents have issued to protect these discoveries. HBOI has a unique frozen repository of marine macro-organisms (many derived from deep-water habitats) and a library of highly enriched fractions derived from these organisms that contain a wide variety of chemical classes and structures. In a pilot project conducted in collaboration with Dr. Chakrabarti of the University of Central Florida (UCF), a sub-set of the HBOI enriched fraction library was screened resulting in the identification of 165 fractions from 85 organisms that reproducibly inhibit the drug resistant Dd2 strain of Plasmodium falciparum at concentrations lower than 5 ¿g/mL. Four series of compounds have already been identified and LC-MS and NMR analysis suggests that many of the remaining active organisms contain novel natural products and are excellent leads for the identification of new chemical scaffolds that can inhibit the malaria parasite. The overarching goal of this collaborative project between Amy Wright of HBOI and Debopam Chakrabarti of UCF is to identify marine invertebrate derived natural products that have utility in the development of new treatments for malaria. The specific goal of this project is to purify and define the structures of the active compounds present in the lead organisms found through our earlier screening project and to further characterize their biological and chemical properties.

描述（由申请人提供）：CDC 估计，2010 年全世界发生了超过 2.16 亿次疟疾临床发作，导致超过 665,000 人死亡（其中超过 86% 的死亡是儿童）。世界上有超过 33 亿人口居住在疟疾的地区。疟疾是可以传播的，虽然疟疾目前在美国并不是一个威胁，但疟原虫按蚊的传播媒介广泛流行，并且仍然存在持续的风险耐药性的出现一直是疟疾治疗中持续存在的问题，鉴于疟疾在全球造成的损失和持续发展，即使是相对较新引入的青蒿素联合疗法也开始产生耐药性。长期以来，天然产物一直是奎宁抗疟药的重要来源，因此识别通过不同作用方式发挥作用并为治疗耐药性疟疾提供治疗选择的新化学实体非常重要。及其合成衍生物，青蒿素及其衍生物，均在前面 海港分院海洋学研究所的海洋生物医学和生物技术研究小组 (HBOI) 自 1984 年以来一直开展海洋天然产品研究项目，并发表了超过 150 种新型生物活性化合物的报告，并已颁发了 100 多项专利来保护这些发现 HBOI 拥有一个独特的高度冷冻的海洋大型生物库（许多来自深水栖息地）和一个从这些生物体中提取的富集组分库，其中含有在与中佛罗里达大学 (UCF) 的 Chakrabarti 博士合作进行的试点项目中，筛选了 HBOI 富集组分库的子集，从 85 个组分中鉴定出 165 个组分。在浓度低于 5 ¿ 时可重复抑制恶性疟原虫 Dd2 耐药菌株的生物体四个系列的化合物已经被鉴定出来，LC-MS 和 NMR 分析表明，许多剩余的活性生物体含有新型天然产物，并且是鉴定可以抑制疟疾寄生虫的新化学支架的极好线索。 HBOI 的 Amy Wright 和 UCF 的 Debopam Chakrabarti 合作项目的目标是确定可用于开发疟疾新疗法的海洋无脊椎动物衍生天然产品。 纯化和定义通过我们早期筛选项目发现的主要生物体中存在的活性化合物的结构，并进一步表征其生物和化学特性。