Journey Sara N, Alden Stephanie L, Hewitt Will M, Peach Megan L, Nicklaus Marc C, Schneekloth John S
Chemical Biology Laboratory , National Cancer Institute , Frederick , MD , USA . Email:
Chemical Biology Laboratory , Basic Science Program , Frederick National Laboratory for Cancer Research , Leidos Biomedical Research Inc. , Frederick , MD , USA.
Medchemcomm. 2018 Oct 5;9(12):2000-2007. doi: 10.1039/c8md00311d. eCollection 2018 Dec 1.
Non-B DNA structures represent intriguing and challenging targets for small molecules. For example, the promoter of the oncogene contains multiple G-quadruplex and i-motif structures, atypical globular folds that serve as molecular switches for gene expression. Of the two, i-motif structures are far less studied. Here, we report the first example of small organic compounds that directly interact with the -1 i-motif. We use a small molecule microarray screen to identify drug-like small molecules that bind to the -1 i-motif but not to several other DNA or RNA secondary structures. Two different lead compounds, and , were discovered to have 7.4 ± 5.3 μM and 5.9 ± 3.7 μM binding affinity by surface plasmon resonance and similar affinity by fluorescence titration. A structure-activity relationship (SAR) was developed and two improved analogues of demonstrated submicromolar binding affinities. Both compounds display pH-dependent binding, indicating that they interact with the DNA only when the i-motif is properly folded. Chemical shift perturbation shows that alters the structure of the i-motif, while has no effect on the i-motif conformation, indicating different modes of interaction.
非B型DNA结构是小分子极具吸引力且具有挑战性的作用靶点。例如，癌基因的启动子包含多个G-四链体和i-基序结构，这些非典型的球状折叠结构充当基因表达的分子开关。在这两者中，对i-基序结构的研究要少得多。在此，我们报道了首例直接与 -1 i-基序相互作用的有机小分子。我们利用小分子微阵列筛选来鉴定与 -1 i-基序结合但不与其他几种DNA或RNA二级结构结合的类药物小分子。通过表面等离子体共振发现两种不同的先导化合物，其结合亲和力分别为7.4 ± 5.3 μM和5.9 ± 3.7 μM，荧光滴定显示它们具有相似的亲和力。建立了构效关系（SAR），并且 的两种改进类似物表现出亚微摩尔级的结合亲和力。两种化合物均表现出pH依赖性结合，表明它们仅在i-基序正确折叠时才与DNA相互作用。化学位移扰动表明 改变了i-基序的结构，而 对i-基序构象没有影响，这表明它们具有不同的相互作用模式。
