核酸双链稳定性的起伏：化学修饰的DNA:RNA双链的结构-稳定性研究
The ups and downs of nucleic acid duplex stability: structure-stability studies on chemically-modified DNA:RNA duplexes.
作者信息
Freier S M, Altmann K H
机构信息
Isis Pharmaceuticals, 2922 Faraday Avenue, Carlsbad, CA 92008, USA.
出版信息
Nucleic Acids Res. 1997 Nov 15;25(22):4429-43. doi: 10.1093/nar/25.22.4429.
Abstract
In an effort to discover novel oligonucleotide modifications for antisense therapeutics, we have prepared oligodeoxyribonucleotides containing more than 200 different modifications and measured their affinities for complementary RNA. These include modifications to the heterocyclic bases, the deoxy-ribose sugar and the phosphodiester linkage. From these results, we have been able to determine structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure. Data for oligonucleotides containing modified pyrimidine nucleotides are presented. In general, modifications that resulted in the most stable duplexes contained a heteroatom at the 2'-position of the sugar. Other sugar modifications usually led to diminished hybrid stability. Most backbone modifications that led to improved hybridization restricted backbone mobility and resulted in an A-type sugar pucker for the residue 5'to the modified internucleotide linkage. Among the heterocycles, C-5-substituted pyrimidines stood out as substantially increasing duplex stability.
摘要
为了发现用于反义治疗的新型寡核苷酸修饰，我们制备了包含200多种不同修饰的寡脱氧核糖核苷酸，并测量了它们与互补RNA的亲和力。这些修饰包括对杂环碱基、脱氧核糖糖和磷酸二酯键的修饰。从这些结果中，我们能够确定将杂交亲和力与寡核苷酸结构变化相关联的构效关系。本文给出了含有修饰嘧啶核苷酸的寡核苷酸的数据。一般来说，导致双链体最稳定的修饰在糖的2'-位含有一个杂原子。其他糖修饰通常会导致杂交稳定性降低。大多数导致杂交改善的主链修饰限制了主链的流动性，并导致修饰的核苷酸间连接5'端残基出现A型糖构象。在杂环中，C-5-取代的嘧啶显著提高了双链体稳定性。
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