Molecular Design of Drugs recognizing Trinucleotide Repeat Sequence.

DNA三核苷酸重复序列，特别是CXG，在人类基因组中很常见。然而，三核苷酸重复序列的扩增与许多疾病有关，包括亨廷顿氏病、脊髓球性肌萎缩症和脊髓小脑共济失调1-4。在这些病例中，已知重复序列长度与发病年龄降低和疾病严重程度相关5,6。（CAG）n、（CTG）n和（CGG）n三核苷酸的重复扩增可能与由X-X不匹配的CXG/CXG三联体组成的替代DNA发夹结构的稳定性增加有关7-11。选择性结合CAG重复序列的小分子配体可以提供确定重复长度的重要探针和研究体内重复序列延伸机制的重要工具。在这里，我们报道了萘啶-阿扎喹诺酮（NA,1）是CAG重复序列的配体，可以用作确定重复序列长度的诊断工具。我们通过核磁共振光谱显示，NA与CAG重复序列的结合诱导了DNA螺旋中胞苷核苷酸的挤压。

DNA trinucleotide repeats, particularly CXG, are common within the human genome. However, expansion of trinucleotide repeats is associated with a number of disorders, including Huntington's disease, spinobulbar muscular atrophy, and spinocerebellar ataxia1-4. In these cases, the repeat length is known to correlate with decreased age of onset and disease severity5,6. Repeat expansion of (CAG)n, (CTG)n, and (CGG)n trinucleotides may be related to the increased stability of alternative DNA hairpin structures consisting of CXG/CXG triads with X-X mismatches7-11. Small molecule ligands that selectively bound to CAG repeats could provide an important probe for determining repeat length and an important tool for investigating the in vivo repeat extension mechanism. Here we report that naphthyridine-azaquinolone (NA,1) is a ligand for CAG repeats and can be used as a diagnostic tool for determining repeat length. We show by NMR spectroscopy that binding of NA to CAG repeats induces extrusion of a cytidine nucleotide from the DNA helix.