Identification of Novel Plant-derived Antimalarial Compounds

新型植物源抗疟化合物的鉴定

• 批准号: 8191020
• 负责人: Tim J Anderson
• 金额: $ 25.78万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191020
• 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. PUBLIC HEALTH RELEVANCE: Malaria is major public health problem, causing over 1 million deaths per year worldwide. The discovery and development of new antimalarial drugs is becoming increasingly urgent as drug- resistant strains become increasingly prevalent. We propose to isolate the active antimalarial compound(s) present in the crude extracts in at least 14 previously uninvestigated plants that have promising antimalarial activity.

描述（由申请人提供）：疟疾是全球热带地区的一个主要公共卫生问题。据估计，每年有5亿人感染疟疾寄生虫，在过去20年中，由于抗药性寄生虫的出现，这一问题更加严重。迫切需要新型抗疟药物。迄今为止，尚未研制出疟疾疫苗，世界许多地区存在对所有类别抗疟药具有抗药性的寄生虫。目前正在采用合理的治疗政策，将联合收割机多种类别的抗疟药物结合起来，以限制耐药性的产生和传播，但遗憾的是，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强效活性的新化合物。几个世纪以来，从植物中分离出的化合物已被证明是抗疟疾治疗的主要药物。用于治疗疟疾的三大类药物是基于植物衍生结构。奎宁最初是从金鸡纳属分离的。并为氯喹和更新的衍生物提供了化学模板。青蒿素最初是从黄花蒿中分离出来的，而以阿托瓦醌为代表的最新一类化合物在结构上衍生自从Tabebuia sp.中分离出来的拉帕酚。人们仍然对可以从植物中鉴定出新的抗疟化合物抱有很好的期望。在初步研究中，我们筛选了一个独特的提取物库，该库来自在南德克萨斯州恶劣环境中茁壮成长的植物。四种粗提取物显示出对疟原虫恶性疟原虫的有效活性，IC 50范围为1.8 - 12.2 μ g/ml。此外，这些提取物在20.5g/ml时对四种哺乳动物细胞系无活性，表明具有良好的选择性指数。这项R21提案旨在分离、鉴定和进一步表征这四种经验证的植物提取物和另外10种提取物的活性成分，这些提取物将从具有抗疟活性的另外46种粗提取物的二次筛选中选出。我们将采购和提取植物材料，提取物将被分馏，并通过生物测定指导分馏鉴定活性成分。疟疾活性化合物的结构将使用核磁共振（NMR）和质谱（MS）确定。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。显示出抗疟疾发展前景的化合物，被定义为对药物敏感和耐药疟疾菌株都有效和有效，并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投入临床开发所需的努力。 疟疾是主要的公共卫生问题，每年在全世界造成100多万人死亡。随着耐药菌株日益普遍，发现和开发新的抗疟药物变得越来越紧迫。我们建议在至少14种以前未研究过的具有抗疟活性的植物中分离出粗提取物中存在的活性抗疟化合物。