DNA HYBRIDS

我们DNA杂交项目的长期目标是找到高度 结合DNA或RNA靶标的特定治疗剂。我们的 方法是用共价杂化分子搜索结构空间 寡聚脱氧核糖核苷酸和非核酸配体。这个 这些杂交种中的寡核苷酸部分提供了靶向亲和力 是我们的光谱监测选择实验所必需的。 它将非核酸配体带入特定的核酸。 基于亲和力轻松进行优化的环境。核磁共振 实验提供了迁入所需的结构信息 以定向的方式组织空间，这是 具有小组合库的选择(2-35个化合物)。最后的 去年，我们用三个复合体进行了实验。一个典型的 课程包括NOESY、TOCSY、DQF-COSY和ID温度系列 使用传统的和基于梯度的实验。这个 氨基酰基杂化W-TGCGCAC在500 MHz的 1月初，如去年的报告所述。我们是 计划再进行一系列实验，以进一步完善 这个结构。第二个复合体是类固醇-DNA杂交体。 (CHL-TGCGCA)2-我们已获得500 MHz、750 MHz和600 MHz的光谱 MHZ，并分配了大部分共振。一个质的结构具有 出现了，这不仅解释了为什么我们的类固醇混合体 极大地提高了亲和力(18千卡/摩尔AAH)、选择性 (RNA/DNA和错配选择性增加&gt；6‘C ATM)和 高染色度(25%-100%取决于序列)，但也表明 甾二胺与苯二胺形成的络合物结构图 富含AT的DNA。这种二胺是一种能与DNA结合的抗生素 几十年来，房地产一直困扰着研究人员。最后，我们有 获得了草酸和DNA杂交物的一系列光谱 在600兆赫。这导致了一种定性的结构， 令人惊讶的是，在DNA的主要沟槽中发现了喹诺酮类药物 不堆叠在暴露的末端碱基对上。我们期待着这些 结果有助于设计新的拓扑异构酶抑制剂。这个 我们的混合动力车的亲和力显著增加(+26‘C ATM (OA-TGCGCA)是朝着缩小差距迈出的一步 寡核苷酸和小分子配体。喹诺酮终末 其分子量为261 Da，提供的亲和力相当于4 额外的A：T碱基对。

The long-term goal of our project on DNA hybrids is to find highly specific therapeutic agents that bind DNA or RNA targets. Our approach is to search structure space with covalent hybrids of oligodeoxyribonucleotides and non-nucleic acid ligands. The oligonucleotide portion in these hybrids provides the target affinity required for our spectrometrically monitored selection experiments. It brings non-nucleic acid ligands into a specific nucleic acid context where it is easily optimized based on affinity. NMR experiments provide the structural information required to move in structure space in a directed way, a feature indispensable for selections with small combinatorial libraries (2-35 compounds). Last year, we performed experiments with three complexes. A typical session included NOESY, TOCSY, DQF-COSY, and ID temperature series with conventional and gradient-based experiments. The aminoacyl-hybrid W-TGCGCAC was studied at 500 MHz at the very beginning of January, as reported in last year's report. We are planning to perform one more series of experiments to further refine this structure. The second complex is that of the steroid-DNA hybrid (chl-TGCGCA)2- We have acquired spectra at 500 MHz, 750 MHz, and 600 MHz and assigned most of the resonances. A qualitative structure has emerged, which not only explains why our steroid-hybrids show dramatically increased affinity (18 kcal/mol AAH), selectivity (RNA/DNA and mismatch selectivity increase >6 'C ATm) and hyperchromicity (25-100% depending on sequence), but also suggests a structural picture for complexes between steroidal diamines and AT-rich DNA. Such diamines are antibiotics whose DNA-binding properties have puzzled research ers for decades. Finally, we have acquired a series of spectra of a hybrid between oxolinic acid and DNA at 600 MHz. This has led to a qualitative structure that, surprisingly, finds the quinolone in the major groove of the DNA and not stacked on the exposed terminal base pair. We expect these results to help the design of new topoisomerase inhibitors. The dramatic increase of affinity seen for our hybrids (+26 'C ATm for OA-TGCGCA) is a step towards closing the gap between oligonucleotideand small molecule-ligands. The quinolone terminus with a molecular weight of 261 Da provides as much affinity as four additional A:T base pairs.