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(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，抗药性寄生虫的出现加剧了这一问题。迫切需要新型抗疟疾药物。到目前为止，还没有开发出疟疾疫苗，世界许多地区都存在对所有种类的抗疟疾药物具有抗药性的寄生虫。结合多种抗疟疾药物的合理治疗政策正被用来限制耐药性的来源和传播，但不幸的是，现有的药物类别不足，无法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的疟疾寄生虫具有强大活性的新化合物。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药物。用于治疗疟疾的三类主要药物是基于植物衍生结构的。奎宁最初是从金鸡纳植物中分离得到的。并为氯喹及较新的衍生物提供了化学模板。青蒿素最初是从青蒿素中分离得到的，以阿托瓦酮为代表的最新化合物是从Tabebuia sp.中分离得到的拉帕霍尔。人们仍然很有希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文库，该文库来自于在南得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作用，IC50范围为1.8~12.2 g/ml，对4种哺乳动物细胞株的IC50为20.5 g/ml，显示出良好的选择性指数。这份R21提案旨在分离、鉴定和进一步鉴定这四种经过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46种额外的具有抗疟疾活性的粗提物中进行二次筛选。我们将采购和提取植物材料，提取的提取物将进行分级，并通过生物测定引导分级鉴定有效成分。抗疟疾活性化合物的结构将通过核磁共振(核磁共振)和质谱学(MS)确定。活性成分将被测试对药物敏感和抗药性疟疾寄生虫和人类细胞的活性。显示出抗疟疾开发前景的化合物将被优先用于药物开发，这些化合物被定义为对药物敏感和抗药性疟疾菌株都有效和有效，并且具有高选择性指数。我们处于有利地位，可以协调将这些化合物转移到临床开发所需的努力。