Molecular Design of Drugs recognizing Trinucleotide Repeat Sequence.

点击翻译按钮获取中文摘要

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.