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.

当新的有效化学类型的药物管道仍然非常低的时候， 据估计，每天有数十个物种正在灭绝，因此有必要建立可用的生物资源库 在现代技术允许评估潜力的情况下，尽可能充分地组装和开采活性天然产品 这些天然产物作为药物先导物或分子研究工具。 该应用程序旨在利用和扩展南非被囊动物（海鞘）的档案 水生生物多样性研究所 (SAIAB)，以及南方海洋收藏的丰富资源 非洲环境观测站网络（SAEON），调查来自非洲的天然产品的潜力 南非被囊类动物及其微生物群作为分子探针和线索应用于癌症和 这个机会支持学生在传染病方面的国际交流和培训。 南非温带东南海岸展示了跨学科的天然产物研究。 大量未经研究的滤食性被囊动物的丰富性和多样性，其中包含复杂的 我们的中心假设是生物多样性和南非特有的被囊动物，而不是 在其他地方发现的，是具有生物活性的新化学型的特别有价值的来源。 初步数据包括分离具有有效生物活性的新代谢物，两个具体目标将 目标：在目标 1 中，将系统地组装被囊类动物提取物和级分的化学库，并 与生物（细胞毒性、抗菌和抗病毒）和化学（LC-MS/MS 和 1H NMR）相关 生物测试将包括抑制真核生物蛋白质分泌的功能测定 （针对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），并抑制病毒进入细胞。目标 2：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 将促进二次生物学研究，支持未来的分子作用机制研究。 除了新的药物先导物和分子研究工具，以及潜在的新化学实体 开发新的合成方法，这项研究预计将提供一个“记录的”库 提取物与生物档案相结合，收集了多达 200 种不同的南非被囊类动物。 将这些数据与源被囊动物的微生物系统发育图谱整合将允许观察 化学分类学、生态和地理模式，并指导未来有针对性的宏基因组分析 用于生物合成研究的微生物共生体群体。

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