Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi

从五大湖真菌中采购生物活性次生代谢物

基本信息

批准号：
9296148
负责人：
Robert Henry Cichewicz
金额：
$ 55.6万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296148
关键词：
Address Adult Affinity Antineoplastic Agents Back Biodiversity Biological Biological Assay Cancer cell line Cells Chemical Warfare Chemicals Chemistry Collaborations Communities Cyclosporins Cytotoxin Data Development Disease Ecology Emotional Environment Exhibits Family Fresh Water Gene Cluster Goals Growth Habitats Hybrids Knowledge Laboratories Lead Libraries Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Medical Methods Michigan Microbiology Mission Molecular Target Natural Products Natural Products Chemistry Nature Pathway interactions Pediatric Oncology Penicillins Pharmaceutical Preparations Pharmacology Preparation Process Production Reporting Research Research Personnel Resources Sampling Solid Source Specificity Talents Taxonomy Techniques Testing The science of Mycology Therapeutic Translating United States National Institutes of Health Water Water Supply Xenograft procedure base benthos bioactive natural products burden of illness design drug discovery fungus improved in vivo inhibitor/antagonist innovation innovative technologies mortality mouse model novel novel therapeutics outcome forecast product development public health relevance scale up screening success tool virtual

项目摘要

DESCRIPTION (provided by applicant): Today, many solid pediatric cancers have a poor prognosis, contributing to an immense amount of physical and emotional suffering on the parts of the victims and their families. A key development on the pathway to addressing this unmet medical need has been growing recognition that the cellular bases of most pediatric cancers are different from those regulating their adult counterparts. Therefore, drug discovery efforts focused on the identification of new therapeutic leads that target the mechanisms underpinning pediatric cancers are needed. Fundamental to the success of any effort for improving chemotherapeutic options against pediatric cancers is an approach that matches the discovery possibilities embodied in a chemically diverse library of drug-like molecules with assays probing the selectivity/specificity of disease-relevant targets. Natural products fulfill this key criterio offering a rich assortment of novel structural features that nature has evolved into bioactive compounds. Our preliminary studies demonstrate that new fungal taxa derived from Great Lakes sediments generate compounds with these types of attractive biological profiles as exemplified in preliminary studies demonstrating selective activity against pediatric cancer cell lines. Based on these data, we hypothesize that the Great Lakes contain a unique and diverse assemblage of fungi that is virtually untapped for the production of bioactive natural products with potential against childhood cancers. To achieve the goal of transforming this fungal source of biological and chemical diversity into therapeutically-promising molecules, we have assembled a collaborative network of researchers with expertise in natural products chemistry, cancer drug discovery/pharmacology, Great Lakes ecology, and mycology. We will test the central hypothesis and fulfill the objectives of this proposal through six specific aims: 1) procuring sediment samples from diverse Great Lakes environments, 2) isolating fungi from sediment samples and preparing an extract library for screening, 3) testing extracts for activities in a suite of new and disease-relevant-assays pertaining to rare yet fatal pediatric cancers, 4) prioritizing bioactive samples for scale-up studies using bioassay data, taxonomic affinity, and chemical markers, 5) purifying bioactive compounds, and 6) verifying the in vivo activities of purified compounds in xenograft mouse models. Several innovative features have been built into our approach that pertain to both the biological assays (focus on selective inhibition of enzymatic and cell targets exhibited by pediatric cancers) and natural products chemistry approaches (new methods for the semi-automated isolation of fungi, expedited extract preparation, and advanced dereplication tools). These new techniques are expected to enhance our approach to identifying new bioactive compounds. Our research is significant because many pediatric cancers remain untreatable and vigorous efforts are needed to identifying compounds with promising therapeutic profiles that address this unmet medical need. We expect that that our studies will provide several new options for further development as therapies for childhood cancers.

描述（由申请人提供）：如今，许多儿童实体癌症的预后较差，给受害者及其家人带来巨大的身心痛苦。解决这一未满足的医疗需求的一个关键进展是，人们越来越认识到大多数儿童癌症的细胞基础与调节成人癌症的细胞基础不同。因此，药物发现工作的重点是确定针对儿科癌症基础机制的新治疗先导药物。改善儿科癌症化疗选择的任何努力取得成功的基础是一种将化学多样化的类药物分子库中体现的发现可能性与探测疾病相关靶标的选择性/特异性的测定相匹配的方法。天然产品满足这一关键标准，提供了丰富多样的新颖结构特征，这些特征已被大自然演变成生物活性化合物。我们的初步研究表明，源自五大湖沉积物的新真菌类群产生的化合物具有这些类型的有吸引力的生物特征，初步研究证明了对儿科癌细胞系的选择性活性。根据这些数据，我们假设五大湖含有独特且多样化的真菌组合，这些真菌实际上尚未开发用于生产具有抗儿童癌症潜力的生物活性天然产品。为了实现将这种生物和化学多样性的真菌来源转化为有治疗前景的分子的目标，我们组建了一个由具有天然产物化学、癌症药物发现/药理学、五大湖生态学和真菌学专业知识的研究人员组成的合作网络。我们将测试中心假设并通过六个具体目标实现该提案的目标：1）从五大湖的不同环境中获取沉积物样本，2）从沉积物样本中分离真菌并准备用于筛选的提取物库，3）测试提取物的活性在一系列与罕见但致命的儿科癌症相关的新的疾病相关测定中，4) 使用生物测定数据、分类亲和力和化学标记优先考虑生物活性样品以进行放大研究，5) 纯化生物活性化合物，以及 6) 验证纯化化合物在异种移植小鼠模型中的体内活性。我们的方法中融入了多项创新功能，涉及生物测定（重点关注儿科癌症所表现出的酶和细胞靶标的选择性抑制）和天然产物化学方法（半自动分离真菌的新方法、快速提取物）准备和高级重复数据删除工具）。这些新技术有望增强我们识别新生物活性化合物的方法。我们的研究意义重大，因为许多儿科癌症仍然无法治疗，需要大力努力来识别具有良好治疗效果的化合物，以满足这一未得到满足的医疗需求。我们期望我们的研究将为进一步开发儿童癌症疗法提供几种新的选择。