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.

在新有效化学型的药物成分保持较低的时候，它是 据估计，每天几十种物种正在灭绝，至关重要的是生物学上的可用存储库 将活性天然产品组装和开采，就像现代技术一样，可以评估潜力 这些天然产物作为药物铅或分子研究工具。目标的目标 申请是要利用和扩大南非的南非膜（腹膜）的档案 水生生物多样性研究所（SAIAB）和南方海洋收集的广泛资源 非洲环境天文台网络（SAEON），以研究天然产品的潜力 南非双线线及其微生物群作为分子探针，并导致用于癌症和 传染病。这个机会支持国际交流和对学生的培训 跨学科天然产品研究。南非东南海岸温度显示 前所未有的抽象和在很大程度上未研究的过滤式膜的多样性，其中包括容纳复合物 微生物财团。我们的中心假设是，生物学上多样化和内在的南非双束缚，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，包括隔离具有潜在生物学活动的新代谢产物，两个具体目标将 被追捕：在AIM 1中，将系统地组装一个贴合的提取物和分数的化学库，并且 与生物学（细胞毒性，抗细菌和抗病毒）和化学（LC-MS/MS和1H NMR）相关 概况。生物测试将包括抑制两种真核生物蛋白质分泌的功能测定 （靶向内质网处的共转运易位）和原核生物（抑制II型 分泌介导的病毒），并抑制病毒进入细胞。在AIM 2中，净化和结构 从优先样品中阐明具有癌症活性的新生物活性天然产物 将促进二级生物学投资，以支持未来的作用研究分子机理。 除了新的药物铅和分子研究工具以及潜在的新化学实体外 开发新的合成方法，这项研究有望提供一个“记录”的库 提取物与生物档案库相结合，以收集多达200种不同的南非双束缚。 将这些数据与源外束的微生物系统发育谱的集成在一起，将允许观察 趋化性，生态和地理模式，并指导未来的靶向元基因组分析 生物合成研究的微生物象征主义种群。

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