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首页> 外文期刊>Journal of Molecular Biology >EFFICIENT INHIBITION OF TRANSCRIPTION ELONGATION IN VITRO BY OLIGONUCLEOTIDE PHOSPHORAMIDATES TARGETED TO PROVIRAL HIV DNA
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EFFICIENT INHIBITION OF TRANSCRIPTION ELONGATION IN VITRO BY OLIGONUCLEOTIDE PHOSPHORAMIDATES TARGETED TO PROVIRAL HIV DNA

机译：靶向HIV HIV DNA的寡核苷酸磷酸酰胺可有效抑制体外转录延伸

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摘要

Tripler-forming oligophosphoramidates containing thymines and cytosines or 5-methyl cytosines (5' T(4)CT(4)C(6)T3') bind strongly to a 16 base-pair oligopurine-oligopyrimidine sequence of HIV proviral DNA even at neutral pH. These triple-helical complexes formed with oligonucleotide analogues with N3'-->P5' phosphoramidate linkages are remarkably stable compared to oligonucleotides with natural phosphodiester linkages. In transcription assays the (T,C)-containing phosphoramidate oligomers induce an efficient arrest of both bacteriophage and eukaryotic transcriptional machineries under conditions where the isosequential phosphodiesters have no inhibitory effect. In both cases the RNA polymerase (SP6, T7 or pol II) is physically blocked by the non-covalent tripler and RNA synthesis is stopped at the tripler site. However the eukaryotic transcription machinery is blocked more efficiently (at submicromolar concentration) than the bacteriophage polymerases. The analysis of the 3'-ends of the truncated transcripts provides evidence for differences in the termination patterns induced by the tripler barrier for the bacteriophage and the eukaryotic systems. This in vitro comparative study provides the basis for the rational design of strong transcriptional inhibitors. The efficient in vitro inhibition obtained using the phosphoramidate oligomers in the eukaryotic transcription assay makes them good candidates for the development of sequence-specific antigene agents. (C) 1996 Academic Press Limited. [References: 51]
机译：包含胸腺嘧啶和胞嘧啶或5-甲基胞嘧啶（5'T（4）CT（4）C（6）T3'）的三聚体形成寡磷酰胺盐即使在中性时也能与16个碱基对的寡嘌呤-寡嘧啶序列牢固结合pH值与具有天然磷酸二酯键的寡核苷酸相比，这些由具有N3'-> P5'氨基磷酸酯键的寡核苷酸类似物形成的三螺旋复合物非常稳定。在转录测定中，在等序磷酸二酯没有抑制作用的条件下，含（T，C）的氨基磷酸亚氨基酯低聚物诱导噬菌体和真核转录机制的有效停滞。在这两种情况下，RNA聚合酶（SP6，T7或pol II）都被非共价三链体物理阻断，RNA合成在三链体位点停止。但是，真核转录机制比噬菌体聚合酶更有效地被封闭（在亚微摩尔浓度）。截短的转录本的3'末端的分析提供了由噬菌体和真核系统的三链体屏障诱导的终止模式差异的证据。这项体外比较研究为合理设计强转录抑制剂提供了基础。在真核转录测定中使用氨基磷酸酯低聚物获得的有效体外抑制作用使其成为开发序列特异性抗原剂的良好候选者。 （C）1996 Academic Press Limited。 [参考：51]

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