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首页> 外文期刊>Biochemistry >Structural and functional characterization of potent antithrombotic oligonucleotides possessing both quadruplex and duplex motifs.
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Structural and functional characterization of potent antithrombotic oligonucleotides possessing both quadruplex and duplex motifs.

机译：具有四链体和双链体基序的有效抗血栓寡核苷酸的结构和功能表征。

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We report the results of a selection for single-stranded DNA oligonucleotide ligands to the serine protease thrombin using recently developed methods. This selection yielded a family of DNA sequences that conform to a consensus structure comprised of a unimolecular quadruplex motif and complementary flanking sequences capable of forming an additional Watson-Crick duplex motif. This novel quadruplex/duplex structure was not reported in a previous selection for DNA molecules which bind to thrombin [Bock et al. (1992) Nature 355, 564-566]. All quadruplex/duplex molecules tested bound to thrombin with higher affinity than quadruplex structures lacking the duplex structure. However, binding affinities did not always correlate with inhibitory potency since some molecules with high affinity were not potent inhibitors in vitro. 1H NMR spectroscopy studies demonstrated that the complementarity of bases in the duplex portion of a selected sequence allows it to form multimolecular structures. Constraining these molecules to the unimolecular quadruplex/duplex structure by bridging the 5' and 3' ends of the duplex motif with either triethylene glycol or disulfide bonds improved their thrombin inhibitory activity. All bridged quadruplex/duplex molecules were more potent inhibitors than molecules with only a quadruplex motif. Bridging the ends of these structures not only increased thrombin inhibition but also improved resistance to nucleases in serum more than 40-fold over the unbridged quadruplex. In addition, we have found that both the length and sequence of the duplex motif are important for inhibition.
机译：我们报告使用最近开发的方法选择丝氨酸蛋白酶凝血酶单链DNA寡核苷酸配体的结果。这种选择产生了符合共有结构的DNA序列家族，该共有序列结构由单分子四链体基序和能够形成另外的Watson-Crick双链体基序的互补侧翼序列组成。这种新颖的四链/双链结构在先前选择的与凝血酶结合的DNA分子中没有报道[Bock等。 （1992）Nature 355，564-566]。所有测试的四链体/双链体分子与凝血酶的结合亲和力高于缺乏双链体结构的四链体结构。然而，结合亲和力并不总是与抑制能力相关，因为一些具有高亲和力的分子在体外并不是有效的抑制剂。 1 H NMR光谱研究表明，所选序列双链体中碱基的互补性使其可以形成多分子结构。通过用三甘醇或二硫键桥接双链体基序的5'和3'末端将这些分子限制为单分子四链体/双链体结构，可改善其凝血酶抑制活性。所有桥接的四链体/双链体分子均比仅具有四链体基序的分子更有效。与未桥接的四链体相比，桥接这些结构的末端不仅增加了对凝血酶的抑制作用，而且使血清中对核酸酶的抗性提高了40倍以上。另外，我们发现双链体基序的长度和序列对于抑制都是重要的。

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