Discovery and Mechanistic Characterization of New Cytotoxic Agents from Marine Cyanobacteria

海洋蓝藻新型细胞毒剂的发现和机理表征

• 批准号: 10533271
• 负责人: Lobna Elsadek
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2023-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533271
• 关键词: Achievement; Actins; Alleles; Anabolism; Antifungal Agents; Area; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biological Process; Biology; Cause of Death; Cell Line; Cell Survival; Cell membrane; Cells; Cessation of life; Chemical Structure; Chemicals; Colorectal Cancer; Complement; Coupled; Coupling; Crystallization; Cyanobacterium; Cytoskeleton; Cytotoxic agent; Cytotoxin; Data; Development; Disease; Dolastatin 10; Drug Industry; Drug Modelings; Environment; Evaluation; FDA approved; Fractionation; Future; Gene Cluster; Goals; HCT116 Cells; Health; Hypoxia Inducible Factor; Investigation; KRAS oncogenesis; Knock-out; Knowledge; Libraries; Lymphoma; Macrolides; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammalian Cell; Mass Spectrum Analysis; Medicine; Membrane; Membrane Potentials; Methods; Microfilaments; Molecular Target; Morphology; National Cancer Institute; Natural Products; Nature; Normal Cell; Organism; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phylogenetic Analysis; Predisposition; Process; Proliferating; Proteins; Proteomics; RNA Interference; Resistance; Role; Sampling; Sedimentation process; Signal Transduction; Site; Source; Specificity; Sterols; Structure; Surface Plasmon Resonance; System; Testing; Therapeutic; Toxic effect; United States; Work; Yeasts; anticancer research; apratoxin; base; cancer cell; cancer therapy; cellular targeting; cytotoxic; cytotoxicity; depolymerization; experimental study; inhibitor; insight; mutant; novel; novel anticancer drug; pathogenic bacteria; pathogenic fungus; pharmacophore; polymerization; polyol; scaffold; screening; small molecule; transcription factor; transcriptome; transcriptome sequencing

Abstract Cancer is a major health problem worldwide and is the second leading cause of death in the United States. Despite the significant advances in cancer research, available therapies still encounter limitations such as resistance, specificity and toxicity, which urgent the discovery of new anticancer agents. Several studies exemplified marine cyanobacteria's role in providing chemically diverse potent cytotoxic agents that act via novel mechanisms. Harnessing the structural space reproduced by marine cyanobacteria in an efficient planned strategy would significantly impact the cancer research field. Therefore, we screen cyanobacterial samples for new/novel cytotoxins and complement our discovery with comprehensive mechanistic studies to assign the therapeutically relevant biological targets. Specifically, samples derived from morphologically and phylogenetically novel cyanobacteria are prioritized for extraction. Extracts are subjected to cancer cell viability assay guided fractionation, coupled with LCMS and NMR dereplication strategies. Structures will be determined using NMR and mass spectrometry. Compounds with intriguing structural novelty and potent or selective activity are subjected to mechanistic characterization. An unbiased assessment of cellular targets is necessary to mine for novel biology/targets. Therefore, we implement universal approaches that could pinpoint perturbed biological pathways and potential molecular targets. In parallel, targeted approaches are employed if structural features of the identified cytotoxin suggest potential pharmacophores with known interacting proteins. We successfully identified targets of the antifungal cytotoxin amantelide A using chemogenomic profiling and targeted approaches. In addition, through the use of an isogenic screening system, we built in selectivity screening in the discovery process to determine if identified new cytotoxins are inhibitors of the oncogenic KRAS and HIF pathways, since these pathways are activated in cancer compared with normal cells. The proposed work will identify new/novel cytotoxic agents that would serve leads to new anticancer therapies. Besides, their assessment as chemical probes would widen our breadth of many biological processes. Finally, this study has the potential to inform new biological target space, which is of tremendous value to cancer research.

摘要 癌症是世界范围内的主要健康问题，并且是美国的第二大死亡原因。 尽管癌症研究取得了重大进展，但可用的治疗方法仍面临局限性，例如 耐药性、特异性和毒性，这迫切需要发现新的抗癌药物。几项研究 举例说明了海洋蓝细菌在提供化学多样性的有效细胞毒性剂中的作用， 新机制。利用海洋蓝藻繁殖的结构空间， 计划中的战略将对癌症研究领域产生重大影响。因此，我们筛选蓝藻 新的/新型细胞毒素的样本，并通过全面的机制研究补充我们的发现， 指定治疗相关的生物靶点。具体而言，样品来源于形态学和 遗传学上新的蓝藻优先提取。提取物经受癌细胞活力 分析指导的分级，结合LCMS和NMR去复制策略。结构将 使用NMR和质谱法测定。具有有趣的结构新奇和有效或 选择性活性受到机械表征。对细胞靶点的无偏评估是 需要挖掘新的生物学/目标。因此，我们采用通用方法， 干扰的生物途径和潜在的分子靶点。与此同时，在下列情况下， 所鉴定的细胞毒素的结构特征表明具有已知相互作用的潜在药效团 proteins.我们成功地确定了目标的抗真菌细胞毒素amantelide A使用化学基因组 特征分析和有针对性的方法。此外，通过使用同基因筛选系统，我们构建了 在发现过程中进行选择性筛选，以确定所鉴定的新细胞毒素是否是 致癌KRAS和HIF途径，因为与正常细胞相比，这些途径在癌症中被激活。 拟议的工作将确定新的/新型细胞毒性药物，将有助于导致新的抗癌疗法。 此外，它们作为化学探针的评估将扩大我们对许多生物过程的广度。最后， 这项研究有可能提供新的生物靶向空间，这对癌症具有巨大价值。 research.