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5亿人感染了疟疾寄生虫，并且在过去20年中，由于抗药性寄生虫的出现，该问题已加剧。迫切需要新型的抗疟药。迄今为止，还没有开发出疟疾疫苗，并且在世界许多地区都存在对所有抗疟药的抗寄生虫。结合多种类抗疟药的合理治疗政策已用于限制耐药性的起源和传播，但不幸的是，没有足够的药物类别来确保这种方法的长期成功。该项目的目的是将新的化合物分离出具有有效活性的新化合物，以抗药物敏感和耐药性疟疾寄生虫。从植物中分离出来的化合物已被证明是抗疟疾疗法的中流型数百年。针对疟疾的三个主要药物类是基于植物来源的结构。奎宁最初是从Cinchona spp中分离出来的。并提供了氯喹和新衍生物的化学模板。青蒿素最初是从Annua的Artemisia分离出来的，由Atovaquone代表的最新化合物是从结构上衍生自lapachol的，它是从Tabebuia sp中分离出来的。人们仍然可以很好地期望从植物中鉴定出新的抗疟疾化合物。在初步研究中，我们筛选了一个独特的提取物库，这些图书馆源自在南德克萨斯州恶劣环境中壮成长的植物。四个粗提物显示出对疟疾寄生虫恶性疟原虫的有效活性，IC50范围为1.8-12.2 <g/ml。此外，这些提取物以20 5G/mL的态度对四个哺乳动物细胞系无活性，表明有良好的选择性指数。该R21提案旨在隔离，识别和进一步表征这四种经过验证的植物提取物的活性成分，以及另外10种提取物，这些提取物将从二级筛选中选择46种具有抗疟疾活性的原油提取物。我们将采购和提取植物材料，提取物将被分馏，并通过生物测定引导的分馏确定的活性成分。疟疾活性化合物的结构将使用核磁共振（NMR）和质谱（MS）确定。活跃成分将被测定用于对药物敏感和耐药性疟疾寄生虫和人类细胞的活性。表现出对抗疟发发育有望的化合物，被定义为对药物敏感和耐药性疟疾菌株和高选择性指数的有效和有效性，将优先用于药物开发。我们在协调将这些化合物转化为临床开发所需的努力方面做得很好。