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    Pseudo-cyclic oligonucleobases
    54.
    发明授权
    Pseudo-cyclic oligonucleobases 失效
    伪循环寡核苷酸

    公开(公告)号：US06383752B1

    公开(公告)日：2002-05-07

    申请号：US09540699

    申请日：2000-03-31

    申请人： Sudhir Agrawal ,  Ekambar R. Kandimalla

    发明人： Sudhir Agrawal ,  Ekambar R. Kandimalla

    IPC分类号： C12Q168

    CPC分类号： C12Q1/6816 ,  C12Q1/6853 ,  C12Q2525/125 ,  C12Q2525/197 ,  C12Q2525/301

    摘要： The present invention comprises a new class of oligonucleobases (e.g., oligonucleotides), which we call “pseudo-cyclic oligonucleotides” (PCOs). PCOs contain two oligonucleotide segments attached through their 3′-3′ or 5′-5′ ends. One of the segments (the “functional segment”) of the PCO has some functionality (e.g., an antisense oligonucleotide complementary to a target mRNA). Another segment (the “protective segment”) is complementary to the 3′- or 5′-terminal end of the functional segment (depending on the end through which it is attached to the functional segment). As a result of complementarity between the functional and protective segment segments, PCOs form intramolecular pseudo-cyclic structures in the absence of the target nucleic acids (e.g., RNA). PCOs are more stable than conventional antisense oligonucleotides because of the presence of 3′-3′ or 5′-5′ linkages and the formation of intramolecular pseudo-cyclic structures. Pharmacokinetic, tissue distribution, and stability studies in mice suggest that PCOs have higher in vivo stability than and, pharmacokinetic and tissue distribution profiles similar to, those of PS-oligonucleotides in general, but rapid elimination from selected tissues. When a fluorophore and quencher molecules are appropriately linked to the PCOs of the present invention, the molecule will fluoresce when it is in the linear configuration, but the fluorescence is quenched in the cyclic conformation. Such oligos are useful for diagnostic purposes.

    摘要翻译： 本发明包括一类新的寡核苷酸（例如寡核苷酸），我们称之为“伪环寡核苷酸”（PCO）。 PCOs含有通过其3'-3'或5'-5'末端连接的两个寡核苷酸片段。 PCO的一个区段（“功能区段”）具有一些功能（例如，与靶mRNA互补的反义寡核苷酸）。 另一段（“保护段”）与功能区段的3'末端或5'末端互补（取决于其连接到功能区段的末端）。 由于功能和保护性片段之间的互补性，PCO在不存在靶核酸（例如RNA）的情况下形成分子内假环状结构。 由于存在3'-3'或5'-5'键并形成分子内假结构，PCO比常规反义寡核苷酸更稳定。 小鼠的药物代谢动力学，组织分布和稳定性研究表明，PCOs的体内稳定性高于药代动力学和组织分布曲线，与通常的PS寡核苷酸类似，但是从选择的组织快速消除。 当荧光团和猝灭剂分子适当地连接到本发明的PCO时，当分子处于线性构型时，分子将发荧光，但荧光在循环构象中淬灭。 这样的寡核苷酸可用于诊断目的。

    Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides
    55.
    发明授权
    Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides 失效
    使用可溶性多聚寡核苷酸的亲和纯化寡核苷酸

    公开(公告)号：US5912332A

    公开(公告)日：1999-06-15

    申请号：US690300

    申请日：1996-07-26

    申请人： Sudhir Agrawal ,  Ivan Habus ,  Ekambar R. Kandimalla

    发明人： Sudhir Agrawal ,  Ivan Habus ,  Ekambar R. Kandimalla

    IPC分类号： C07H1/06 ,  C07H21/00 ,  C12Q1/68

    CPC分类号： C07H21/00 ,  C07H1/06

    摘要： The present invention provides novel compounds and methods for purifying oligonucleotides. The compounds according to the invention are multimeric oligonucleotides comprising a multimerization domain for inducing multimeric oligonucleotide aggregation, a hybridization domain that is complementary to a target oligonucleotide whose isolation is desired, and a linker domain connecting the multimerization domain and the hybridization domain. Other compounds of the invention comprise dendrimers having oligonucleotides with hybridization domains linked thereto.The methods of the invention comprise contacting the compounds of the invention with a solution containing a target oligonucleotide whose purification is desired. The target oligonucleotide hybridizes to the hybridization domain of the inventive compounds, thereby forming an aggregate. Synthetic failure sequences (N-1, N-2, etc.) and other oligonucleotides not complementary to the hybridization domain do not hybridize with the hybridization domain of the compounds and remain free in solution. Conventional size exclusion chromatography or small pore filter membranes are then used to separate the aggregate (and hence target oligonucleotide) from the other oligonucleotides. The aggregate is denatured and the target oligonucleotide separated once again by size exclusion chromatography or with a small pore filter membrane.

    摘要翻译： 本发明提供了用于纯化寡核苷酸的新型化合物和方法。 根据本发明的化合物是多聚寡核苷酸，其包含用于诱导多聚寡核苷酸聚集的多聚化结构域，与需要分离的靶寡核苷酸互补的杂交结构域和连接多聚化结构域和杂交结构域的连接体结构域。 本发明的其它化合物包含具有与其连接的杂交结构域的寡核苷酸的树枝状大分子。 本发明的方法包括使本发明的化合物与含有需要纯化的靶寡核苷酸的溶液接触。 靶寡核苷酸与本发明化合物的杂交结构域杂交，从而形成聚集体。 合成失败序列（N-1，N-2等）和与杂交结构域不互补的其他寡核苷酸不与化合物的杂交结构域杂交并且在溶液中保持游离。 然后使用常规尺寸排阻色谱法或小孔过滤膜将聚集体（因此靶寡核苷酸）与其他寡核苷酸分离。 聚集体变性，并且目标寡核苷酸再次通过尺寸排阻色谱法或用小孔滤膜分离。