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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Antisense inhibition of Flk-1 by oligonucleotides composed of 2'-deoxy-2'-fluoro-beta-D-arabino- and 2'-deoxy-nucleosides.
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Antisense inhibition of Flk-1 by oligonucleotides composed of 2'-deoxy-2'-fluoro-beta-D-arabino- and 2'-deoxy-nucleosides.

机译：由2'-脱氧-2'-氟-β-D-阿拉伯糖和2'-脱氧核苷组成的寡核苷酸对Flk-1的反义抑制。

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The design of new antisense oligomers with improved binding affinity for targeted RNA, while still activating RNase H, is a major research area in medicinal chemistry. RNase H recognizes the RNA-DNA duplex and cleaves the complementary mRNA strand, providing the main mechanism by which antisense oligomers elicit their activities. It has been shown that configuration inversion at the C2' position of the DNA sugar moiety (arabinonucleic acid, ANA), combined with the substitution of the 2'OH group by a fluorine atom (2'F-ANA) increases the oligomer's binding affinity for targeted RNA. In the present study, we evaluated the antisense activity of mixed-backbone phosphorothioate oligomers composed of 2'-deoxy-2'-fluoro-beta-D-arabinose and 2'-deoxyribose sugars (S-2'F-ANA-DNA chimeras). We determined their abilities to inhibit the protein expression and phosphorylation of Flk-1, a vascular endothelial growth factor receptor (VEGF), and VEGF biological effects on endothelial cell proliferation, migration, and platelet-activating factor synthesis. Treatment of endothelial cells with chimeric oligonucleotides reduced Flk-1 protein expression and phosphorylation more efficiently than with phosphorothioate antisenses (S-DNA). Nonetheless, these two classes of antisenses inhibited VEGF activities equally. Herein, we also demonstrated the capacity of the chimeric oligomers to elicit RNase H activity and their improved binding affinity for complementary RNA as compared with S-DNA.
机译：设计新的反义寡聚体，其对靶RNA的结合亲和力提高，同时仍激活RNase H，是药物化学领域的主要研究领域。 RNase H识别RNA-DNA双链体并切割互补的mRNA链，从而提供了反义寡聚物引发其活性的主要机制。已经显示，DNA糖部分（阿拉伯糖核酸，ANA）的C2'位置的构型反转，与2'OH基团被氟原子（2'F-ANA）取代相结合，增加了低聚物的结合亲和力靶向RNA。在本研究中，我们评估了由2'-脱氧-2'-氟-β-D-阿拉伯糖和2'-脱氧核糖（S-2'F-ANA-DNA嵌合体）组成的混合骨干硫代磷酸酯低聚物的反义活性）。我们确定了它们抑制Flk-1，血管内皮生长因子受体（VEGF）的蛋白质表达和磷酸化的能力，以及VEGF对内皮细胞增殖，迁移和血小板活化因子合成的生物学作用。与硫代磷酸酯反义（S-DNA）相比，用嵌合寡核苷酸处理内皮细胞可更有效地降低Flk-1蛋白的表达和磷酸化。尽管如此，这两类反义物同样抑制VEGF活性。在本文中，我们还证明了与S-DNA相比，嵌合寡聚体引发RNase H活性的能力及其对互补RNA的改善的结合亲和力。

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