Identification of Novel Plant-derived Antimalarial Compounds

新型植物源抗疟化合物的鉴定

• 批准号: 8298963
• 负责人: Tim J Anderson
• 金额: $ 20.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298963
• 关键词: Antimalarials; Area; Artemisia annua; Artemisinins; Biological; Biological Assay; Biological Availability; Cell Line; Cells; Cessation of life; Chemicals; Chloroquine; Cinchona; Clinical; Crude Extracts; Data; Development; Disease; Drug resistance; Drug-sensitive; Ensure; Environment; Epithelial Cells; Event; Fractionation; Goals; Human; Inhibitory Concentration 50; Joints; Laboratories; Lead; Libraries; Malaria; Malaria Vaccines; Mammalian Cell; Mass Spectrum Analysis; Mefloquine; Multi-Drug Resistance; Myanmar; Nuclear Magnetic Resonance; Oral; Parasite resistance; Parasites; Parasitic Diseases; Pharmaceutical Preparations; Pharmacologic Substance; Pittosporum; Plant Extracts; Plants; Plasmodium falciparum; Policies; Positioning Attribute; Public Health; Quinine; Recording of previous events; Rhus; Screening procedure; South Texas; Spectrum Analysis; Structure; Tabebuia; Techniques; Testing; Thailand; Toxic effect; artemisinine; atovaquone; base; cost; drug development; drug discovery; expectation; fight against; indexing; novel; programs; resistant strain; success

DESCRIPTION (provided by applicant): Malaria is a major public health problem in tropical regions worldwide. It is estimated that 500 million people are infected with malarial parasites annually and the problem has been exacerbated in the past 20 years by the emergence of drug resistant parasites. There is an urgent need for novel classes of antimalarial drugs. To date no malaria vaccine has been developed and parasites resistant to all classes of antimalarials exist in many areas of the world. Rational treatment policies that combine multiple classes of antimalarial drugs are being used to limit the origin and spread of drug resistance, but unfortunately there are insufficient drug classes available to ensure the long term success of this approach. The goal of this project is to isolate new chemical compounds with potent activity against drug sensitive and drug resistant malarial parasites. Compounds isolated from plants have proven to be the mainstay in antimalarial therapy for centuries. Three major drug classes in use against malaria are based on plant-derived structures. Quinine was originally isolated from Cinchona spp. and provided the chemical template for chloroquine and newer derivatives. Artemisinin was originally isolated from Artemisia annua and the newest class of compounds represented by atovaquone is structurally derived from lapachol, isolated from Tabebuia sp. There remains a good expectation that new antimalarial compounds can be identified from plants. In preliminary studies we screened a unique extract library derived from plants that thrive in the harsh environment of South Texas. Four crude extracts showed potent activity against the malaria parasite P. falciparum with an IC50 range of 1.8 - 12.2 <g/ml. Furthermore, these extracts were inactive against four mammalian cell lines at 20 5g/ml, suggesting a good selectivity index. This R21 proposal aims to isolate, identify and further characterize the active components of these four validated plant extracts and an additional 10 extracts that will be selected from secondary screening of 46 additional crude extracts with antimalarial activities. We will procure and extract the plant material and the extracts will be fractionated and the active constituents identified by bioassay-guided fractionation. The structures of the malarial-active compounds will be determined using nuclear magnetic resonance (NMR) and mass spectroscopy (MS). The active constituents will be assayed for activity against drug sensitive and drug resistant malaria parasites and human cells. Compounds that show promise for antimalarial development, defined as potent and effective against both drug sensitive and drug resistant malaria strains and a high selectivity index, will be prioritized for drug development. We are well positioned to coordinate efforts needed to move these compounds into clinical development.

描述（由申请人提供）：疟疾是全球热带地区的主要公共卫生问题。据估计，每年有5亿人感染疟疾寄生虫，在过去20年中，由于出现了耐药寄生虫，这一问题更加严重。迫切需要新型抗疟疾药物。迄今为止，还没有研制出疟疾疫苗，而且在世界许多地区都存在对所有种类的抗疟药具有耐药性的寄生虫。目前正在使用结合多种抗疟药物的合理治疗政策来限制耐药性的起源和传播，但不幸的是，现有的药物类别不足以确保这一方法的长期成功。该项目的目标是分离出对药物敏感和耐药疟疾寄生虫具有有效活性的新化合物。几个世纪以来，从植物中分离出来的化合物已被证明是抗疟疾治疗的主要成分。目前用于治疗疟疾的三种主要药物都是基于植物衍生的结构。奎宁最初是从金鸡纳属植物中分离得到的，为氯喹及其新衍生物提供了化学模板。青蒿素最早从黄花蒿中分离得到，而以阿托伐醌为代表的最新一类化合物在结构上是从塔伯布亚属植物中分离得到的拉帕恰尔。从植物中鉴定新的抗疟化合物仍有很大希望。在初步研究中，我们筛选了一个独特的提取物库，这些提取物来自于在南德克萨斯州恶劣环境中茁壮成长的植物。4种粗提物对恶性疟原虫有较强的抑制活性，IC50范围为1.8 ~ 12.2 <g/ml。在浓度为20 5g/ml时，对4种哺乳动物细胞系均无活性，具有良好的选择性。本R21提案旨在分离、鉴定和进一步表征这四种经过验证的植物提取物的活性成分，以及将从另外46种具有抗疟活性的粗提取物的二次筛选中选择的另外10种提取物。我们将获取并提取植物材料，提取物将被分离，并通过生物测定引导分离鉴定活性成分。疟疾活性化合物的结构将通过核磁共振（NMR）和质谱（MS）来确定。将测定活性成分对药物敏感和耐药疟疾寄生虫和人类细胞的活性。那些显示出抗疟疾开发前景的化合物，被定义为对药物敏感和耐药疟疾菌株都有效且具有高选择性指数，将优先用于药物开发。我们有能力协调将这些化合物推向临床开发所需的努力。