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

• 批准号: 8697723
• 负责人: Robert Henry Cichewicz
• 金额: $ 58.96万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697723
• 关键词: Address; Adult; Affinity; Antineoplastic Agents; Back; Biodiversity; Biological; Biological Assay; Biological Factors; 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; Mission; Molecular Target; Natural Products Chemistry; Nature; Pathway interactions; Pediatric Oncology; Penicillins; Pharmaceutical Preparations; Pharmacology; Preparation; Process; Production; Reporting; Research; Research Personnel; Resources; Sampling; Solid; Source; Specificity; Taxon; Techniques; Testing; The science of Mycology; Therapeutic; Translating; United States National Institutes of Health; Water; Water Supply; Xenograft procedure; base; benthos; burden of illness; design; drug discovery; fungus; improved; in vivo; inhibitor/antagonist; innovation; innovative technologies; mortality; mouse model; novel; novel strategies; novel therapeutics; outcome forecast; product development; public health relevance; scale up; screening; success; tool

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，许多扎实的小儿癌症的预后较差，造成了受害者及其家人的巨大身体和情感痛苦。满足这种未满足的医学需求的途径的关键发展是越来越认识到，大多数儿科癌症的细胞基础与调节成人同行的癌症不同。因此，需要鉴定需要针对基于儿科癌症的机制的新治疗铅的药物发现工作。为了改善针对儿科癌症的化学治疗选择的任何努力的成功，是一种与化学多样性类似药物样分子库中的发现可能性相匹配的方法，并探测了探测疾病相关靶标的选择性/特异性的测定。天然产品符合此关键标准，提供了各种大自然已经演变成生物活性化合物的新型结构特征。我们的初步研究表明，源自大湖区沉积物的新真菌分类单元与这些类型的有吸引力的生物学特征产生化合物，例如在初步研究中表明针对儿科癌细胞系的选择性活性。基于这些数据，我们假设大湖区包含一种独特而多样化的真菌组合，实际上未开发，用于生产具有童年癌症潜力的生物活性天然产品。为了实现将这种生物学和化学多样性的真菌来源转化为治疗分子的目标，我们组建了一个与自然产品化学，癌症药物发现/药理学，大湖泊生态学和真菌学专业知识的研究人员的协作网络。我们将通过六个特定目的测试中心假设，并实现该提案的目标：1）从各种大湖泊环境中采购沉积物样本，2）从沉积物样本中隔离真菌，并准备提取物库进行筛查，3）测试提取物进行活动以进行活动以进行活动以进行活动 在与罕见但致命的儿科癌症有关的新的和疾病的新指数中，4）使用生物测定数据，分类学亲和力和化学标志物对生物活性样本进行优先研究，5）净化生物活性化合物，6）验证Xenerigraft in XeneGraft in XeneRagts In Vivo Active in vivo Aspive。我们的方法中内置了几种与生物测定有关的创新特征（侧重于对酶促的选择性抑制和小儿癌所表现出的细胞靶标）和天然产品化学方法（用于半自动化的真菌分离的新方法，真菌，快速提取的提取物和先进的消毒工具）。这些新技术有望增强我们识别新生物活性化合物的方法。我们的研究很重要，因为许多儿科癌症仍然无法治疗，并且需要竭尽全力来识别具有有希望的治疗特征的化合物，以满足这种未满足的医疗需求。我们预计我们的研究将为童年癌症的疗法提供几种新的选择，以进一步发展。