Vaden Rachel M, Oswald Nathaniel W, Potts Malia B, MacMillan John B, White Michael A
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Mar Drugs. 2017 Mar 15;15(3):75. doi: 10.3390/md15030075.
Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, ⁶,⁶-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule's breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction.
自然界中发现的化学物质经过地质时间尺度的演化，能够与生物分子进行有效相互作用，因此是药物开发的有效资源。海洋来源的细菌是化学性质多样的生物活性次生代谢产物的丰富来源，但将这种多样性用于生物医学益处受到与天然产物纯化和生化机制确定相关挑战的限制。使用功能特征本体（FUSION），我们报告了一种海洋来源天然产物6,6-二甲基腺苷的平行分离和表征，该产物能强烈抑制多种非小细胞肺癌细胞系中的AKT信号传导。在通过与市售样品比较验证所阐明的结构后，开始进行实验以了解该小分子在生物环境中的作用广度。其中一个实验，对50多种激酶进行的反相蛋白质阵列（RPPA）分析，表明了对治疗的特定细胞反应。总之，利用FUSION平台能够快速生成并验证未知天然产物的生物作用机制假设，并允许从化学复杂的组分中加速纯化生物活性成分。
