Natural Product Drug Discovery from South African Tunicates by Leveraging International Training Opportunities

利用国际培训机会从南非被囊动物中发现天然产物药物

• 批准号: 9232752
• 负责人: Kerry Leigh McPhail
• 金额: $ 40.49万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232752
• 关键词: Anti-Bacterial Agents; Antineoplastic Agents; Antiviral Agents; Aquaculture; Archives; Bacteria; Bacterial Infections; Biochemical; Biodiversity; Biological; Biological Assay; Biological Testing; Biology; Biomedical Research; Cells; Chemicals; Chemistry; Collaborations; Collection; Communicable Diseases; Complex; Coupled; Cytotoxin; DNA; Data; Data Analyses; Databases; Development; Dinosaurs; Disease; Endoplasmic Reticulum; Equipment and supply inventories; Eukaryota; Exhibits; Extinction (Psychology); Funding; Future; Geography; Goals; Health; Human; Institutes; International; Investigation; Laboratories; Laboratory culture; Libraries; Malignant Neoplasms; Marine Invertebrates; Marines; Mediating; Metagenomics; Methodology; Methods; Microbial Genetics; Microbial Taxonomy; Microbiology; Modernization; Molecular; Molecular Genetics; Molecular Mechanisms of Action; Molecular Probes; Morphology; Multi-Drug Resistance; Natural Product Drug; Natural Products; Organism; Pattern; Pharmacologic Substance; Phylogenetic Analysis; Population; Prokaryotic Cells; Protein Inhibition; Protein Secretion; Research; Research Personnel; Resources; Sampling; Signal Transduction; Source; South Africa; South African; Structure; Structure-Activity Relationship; Surveys; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Training; Universities; Urochordata; Viral; Virulence; Virus Diseases; Yondelis; alpha Toxin; ascidian; bacterial resistance; base; cancer cell; cytotoxic; cytotoxicity; data acquisition; data integration; data mining; design; drug discovery; educational atmosphere; feeding; genetic resource; human disease; inhibitor/antagonist; insight; instrumentation; marine natural product; marine organism; metabolomics; microbial; microbial community; microbiota; pathogen; repository; small molecule libraries; student training; tool; training opportunity

At a time when pharmaceutical pipelines of new efficacious chemotypes remain critically low, and it is estimated that dozens of species are going extinct daily, it is essential that available repositories of biologically active natural products be assembled and mined as fully as modern technologies allow to assess the potential of these natural products as pharmaceutical leads or molecular research tools. The objectives of this application are to leverage and expand an archive of South African tunicates (ascidians) at the South African Institute of Aquatic Biodiversity (SAIAB), and the extensive resources for marine collections of the South African Environmental Observatory Network (SAEON), to investigate the potential of natural products from South African tunicates and their microbiota as molecular probes and leads for application in cancer and infectious diseases. This opportunity supports international exchange and training of students in interdisciplinary natural products research. The temperate southeastern coast of South Africa exhibits an unprecedented abundance and diversity of largely unstudied filter-feeding tunicates, which house complex microbial consortia. Our central hypothesis is that biologically diverse and endemic South African tunicates, not found elsewhere, are a particularly valuable source of biologically active new chemotypes. Guided by preliminary data that includes isolation of new metabolites with potent biological activities, two specific aims will be pursued: In aim 1, a chemical library of tunicate extracts and fractions will be systematically assembled and associated with biological (cytotoxicity, anti-bacterial and anti-viral) and chemical (LC-MS/MS and 1H NMR) profiles. Biological testing will include functional assays for inhibition of protein secretion in both eukaryotes (targeting cotranslational translocation at the endoplasmic reticulum) and prokaryotes (inhibition of Type II Secretion-mediated virulence), and inhibition of viral entry into cells. In aim 2, purification and structure elucidation of new biologically active natural products, with a focus on cancer activity, from prioritized samples will facilitate secondary biological investigation that will support future molecular mechanism of action studies. In addition to new pharmaceutical leads and molecular research tools, and new chemical entities for potential development of new synthetic methodologies, this research is expected to provide a “documented” library of extracts coupled to a biological archive for a collection of up to 200 different South African tunicates. Integration of these data with microbial phylogenetics profiles of the source tunicates will allow observation of chemotaxonomic, ecological and geographical pattern, and guide future targeted metagenomic analyses of microbial symbiont populations for biosynthetic investigations.

在新的有效化学型的药物管道仍然非常低的时候， 据估计，每天都有数十种物种灭绝，因此， 活性天然产品应尽可能充分地收集和开采，以评估现代技术的潜力。 这些天然产物作为药物先导或分子研究工具。这一目标 应用程序是利用和扩大档案的南非被囊动物（海鞘）在南非 水生生物多样性研究所（SAIAB），以及南方海洋收藏的广泛资源 非洲环境观测站网络，调查非洲自然产品的潜力， 南非被囊类动物及其微生物群作为分子探针和在癌症和 传染病这个机会支持学生的国际交流和培训， 跨学科的天然产物研究。南非温和的东南海岸 前所未有的丰富和多样性，主要是未经研究的滤食性被囊动物，其中房屋复杂 微生物群落我们的中心假设是，生物多样性和特有的南非被囊动物，而不是 在其他地方发现的，是生物活性新化学型的特别有价值的来源。指导 初步数据，包括分离新的代谢产物与强大的生物活性，两个具体的目标将 在目标1中，将系统地组装被囊动物提取物和级分的化学文库， 与生物（细胞毒性、抗菌和抗病毒）和化学（LC-MS/MS和1H NMR）相关 数据区.生物学试验将包括抑制两种真核生物蛋白分泌的功能试验 （靶向内质网的共翻译易位）和原核生物（抑制II型 分泌介导的毒力），以及抑制病毒进入细胞。在目标2中，纯化和结构 从优先样品中阐明新的生物活性天然产物，重点关注癌症活性 这将有助于二次生物学研究，支持未来的分子作用机制研究。 除了新的药物线索和分子研究工具，以及新的化学实体， 随着新合成方法的开发，这项研究预计将提供一个“有记录的”库， 提取物再加上一个生物档案馆收集多达200种不同的南非被囊动物。 将这些数据与源被囊动物的微生物遗传学谱相结合，将允许观察 化学分类，生态和地理模式，并指导未来有针对性的宏基因组分析， 微生物共生体种群进行生物合成研究。

项目成果

New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors.

新的曼德拉内酯扩展了大环内酯系列线粒体抑制剂。

• DOI: 10.1021/acs.jmedchem.7b00990
• 发表时间: 2017
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Nazari,Mohamad;Serrill,JeffreyD;Wan,Xuemei;Nguyen,MinhH;Anklin,Clemens;Gallegos,DavidA;Smith3rd,AmosB;Ishmael,JaneE;McPhail,KerryL
• 通讯作者: McPhail,KerryL

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.

• DOI: 10.3390/md20070418
• 发表时间: 2022-06-27
• 期刊: Marine drugs
• 影响因子: 5.4