Discovery of Marine Invertebrate-Derived Antimalarial Agents

描述（由申请人提供）：CDC估计，2010年全球发生了超过2.16亿例疟疾临床发作，超过665，000例死亡（其中超过86%的死亡是儿童）。世界上有超过33亿人口生活在疟疾传播的地区，尽管疟疾目前在美国不是一个威胁，但寄生虫的传播媒介按蚊广泛流行，疟疾重新引入美国的风险仍然存在。抗药性的出现一直是疟疾治疗中的一个问题，即使是相对较新采用的青蒿素综合疗法也开始产生抗药性。鉴于全球疟疾死亡人数和抗药性的持续发展，必须确定通过不同作用模式发挥作用并为治疗抗药性疟疾提供治疗选择的新化学实体。天然产物一直是抗疟疾药物的重要来源，奎宁及其合成衍生物，青蒿素及其衍生物， 疟疾的一线治疗。海港海洋学研究所分支海洋生物医学和生物技术研究小组（HBOI）自1984年以来一直在进行海洋天然产物研究计划，并已发表了150多种新型生物活性化合物的报告，并颁发了100多项专利来保护这些发现。HBOI拥有一个独特的海洋大型生物（许多来自深水栖息地）冷冻库和一个来自这些生物的高度浓缩组分库，这些生物含有各种化学类别和结构。在与中央佛罗里达大学（UCF）的Chakrabarti博士合作进行的一个试验项目中，筛选了HBOI富集级分文库的子集，结果鉴定了来自85种生物体的165个级分，这些级分在低于5 μ g/mL的浓度下可重复抑制恶性疟原虫的抗药性Dd 2菌株。已经鉴定了四个系列的化合物，LC-MS和NMR分析表明，许多剩余的活性生物体含有新的天然产物，并且是鉴定可以抑制疟疾寄生虫的新化学支架的极好的线索。HBOI的Amy Wright和UCF的Debopam Chakrabarti之间的这个合作项目的首要目标是确定海洋无脊椎动物衍生的天然产品，这些产品在开发疟疾新疗法方面具有实用性。该项目的具体目标是 以纯化和确定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。

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.