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首页> 外文期刊>RSC Advances >Clickable trimethylguanosine cap analogs modified within the triphosphate bridge: synthesis, conjugation to RNA and susceptibility to degradation
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Clickable trimethylguanosine cap analogs modified within the triphosphate bridge: synthesis, conjugation to RNA and susceptibility to degradation

机译：在三磷酸桥内改性的可点击三甲基胍帽模拟：合成，与RNA的缀合和降解的易感性

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The trimethylguanosine (m _(3) G) cap present at the 5′ end of small nuclear RNAs (snRNAs) has been proposed as an effective nuclear localization signal (NLS) for nucleus-targeting therapeutics such as antisense oligonucleotides. To provide novel tools for studies on m _(3) G-mediated transport and m _(3) G degradation, we synthesized a series of novel m _(3) G cap analogs that combine modifications potentially affecting its activity as an NLS and stability in vivo with a modification enabling simple conjugation to biomolecules. The synthesized dinucleotide m _(3) G analogs carry a single phosphate-modification (phosphorothioate, methylenebisphosphonate or imidodiphosphate) at the selected position of the triphosphate bridge in order to increase their resistance to enzymatic cleavage and a (2-azidoethyl)-carbamoylmethyl group at the 2′-position of adenosine as a second nucleotide to enable conjugation to alkyne-containing biomolecules by copper catalyzed azide–alkyne cycloaddition (CuAAC). The susceptibility of m _(3) G cap analogs to non-specific and specific degradation was studied in fetal bovine serum and in an in vitro decapping assay with hNUDT16 enzyme, respectively. The susceptibility of m _(3) G cap analogs to hNUDT16 mediated decapping was also determined after their CuAAC-mediated conjugation to a model oligonucleotide bearing a 5′-alkyne group. Depending on the type and the position of introduced modifications, they modulate the susceptibility to specific and non-specific degradation of conjugated molecules to various extent, with O to NH substitution at the α/β position providing the greatest m _(3) G stability against hNUDT16.
机译：已经提出了在5'核RNA（SNRNA）的5'末端（SNRNA）的三甲基胍（M _（3）G）帽作为核靶向治疗剂如反义寡核苷酸的有效核定位信号（NLS）。为了提供关于M _（3）G介导的转运和M _（3）G降解研究的新型工具，我们合成了一系列新的M _（3）G帽类似物，其将可能影响其活性的修改与NLS相结合。体内稳定性具有改进，使得生物分子能够简单的缀合。合成的二核苷酸M _（3）G类似物在三磷酸桥的选定位置携带单一的磷酸盐 - 改性（硫代磷酸甲酯，亚磷酸二膦酸盐或咪唑膦酸），以提高其对酶切割的抵抗力和（2-氮乙基） - 氨基甲酰基在腺苷的2'-位置作为第二核苷酸，以通过铜催化的叠氮化物 - 炔烃环加入（Cuaac）将含炔的生物分子缀合。在胎儿牛血清中研究了M _（3）G帽模数与非特异性和特异性降解的敏感性，并分别用HNUDT16酶进行体外拆卸测定。在其Cuaac介导的含有5'-炔基组的模型寡核苷酸之后，也确定M _（3）G帽模拟到HNUDT16介导的沉积的敏感性。根据引入的修饰的类型和位置，它们调节对缀合分子的特异性和非特异性降解到各种程度的敏感性，在α/β位置以NH替换提供最大的M _（3）G稳定性反对HNUDT16。

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