RNA-binding affinities and crystal structure of oligonucleotides containing five-atom amide-based backbone structures
RNA-binding affinities and crystal structure of oligonucleotides containing five-atom amide-based backbone structures
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DOI：
10.1021/bi060354o
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发表时间：
2006-07-04
期刊：
影响因子：
2.9
通讯作者：
Egli, Martin
中科院分区：
文献类型：
--
作者：
Pallan, Pradeep S.;von Matt, Peter;Egli, Martin
在过去二十年中研究的数百种核酸类似物中，只有很少的主链在残基之间具有比连接DNA和RNA中糖环部分的四原子接头O3 '-P-O 5'-C5'更短或更长的接头。据报道，通过五原子接头O3 '-CH*（CH 3）-CO-NH-CH 2（* 表示手性中心）连接的2'-脱氧核糖核苷二聚体仅导致RNA-DNA杂交体的轻微不稳定，其中DNA链包含一种或多种这些酰胺连接的二聚体（De Napoli，L.，Iadonisi，A.，Montesarchio，D.，瓦拉，M.，和Piccialli，G.（1995）含有新核苷间酰胺键的胸苷二聚体的合成及其并入寡脱氧核糖核苷酸，Bioorg。医学化学快报5，1647-1652）。为了分析这种五原子酰胺接头的各种化学性质对修饰的DNA链的RNA结合亲和力的影响，我们合成了五种不同的酰胺连接的二聚体，包括具有X3 '-C*H（CH 3）-CO-NH-CH 2（X）O，CH 2）类型的纯手性接头的结构以及在3'-核苷的2 '-位携带甲氧基的相应类似物。我们已经进行了详细的热力学分析的双链体形成之间的修饰的DNA和RNA，与DNA链之间含有一个和七个连续的修饰的二聚体。与天然DNA相比，一些五原子连接的二聚体导致显著更高的RNA结合亲和力。有趣的是，在手性中心具有相反立体化学的接头在不同程度上稳定修饰的DNA和RNA之间的双链体。溶液中的CD光谱和具有单个酰胺连接的二聚体的RNA-DNA双链体的晶体结构表明，较长的酰胺主链不会破坏双链体的几何形状。这些观察结果提供了进一步的证据，表明两种不同类型的核酸之间的稳定交叉配对不需要连接其单个残基的原子数量匹配。
Among the hundreds of nucleic acid analogues that have been studied over the last two decades only very few exhibit backbones with linkers between residues that are either shorter or longer than the four-atom linker O3'-P-O5'-C5' connecting sugar ring moieties in DNA and RNA. 2'-Deoxyribonucleoside dimers connected by a five-atom linker O3'-CH*(CH3)-CO-NH-CH2 (* designates a chiral center) were reported to lead to only a slight destabilization of RNA-DNA hybrids in which the DNA strand contained one or several of these amide-linked dimers (De Napoli, L., Iadonisi, A., Montesarchio, D., Varra, M., and Piccialli, G. (1995) Synthesis of thymidine dimers containing a new internucleosidic amide linkage and their incorporation into oligodeoxyribonucleotides, Bioorg. Med. Chem. Lett. 5, 1647-1652). To analyze the influence of various chemistries of such five-atom amide linkers on the RNA-binding affinity of modified DNA strands, we have synthesized five different amide-linked dimers, including structures with homochiral linkers of the type X3'-C*H(CH3)-CO-NH-CH2 (X) O, CH2) as well as the corresponding analogues carrying methoxy groups at the 2'- position of the 3'-nucleosides. We have conducted a detailed thermodynamic analysis of duplex formation between the modified DNA and RNA, with the DNA strands containing between one and seven consecutive modified dimers. Some of the five-atom-linked dimers lead to significantly higher RNA-binding affinities compared with that of native DNA. Interestingly, the linkers with opposite stereochemistry at the chiral center stabilize duplexes between the modified DNA and RNA to different degrees. CD spectroscopy in solution and a crystal structure of an RNA-DNA duplex with a single amide-linked dimer demonstrate that the longer amide backbones do not disrupt the duplex geometry. These observations provide further evidence that stable cross-pairing between two different types of nucleic acids does not require the numbers of atoms linking their individual residues to match.