Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, USA.
J Am Chem Soc. 2011 Apr 27;133(16):6343-51. doi: 10.1021/ja2003878. Epub 2011 Mar 31.
Small interfering double-stranded RNAs have been synthesized bearing one or more base modifications at nucleotide positions 4, 11, and/or 16 in the guide strand. The chemically modified base is an N(2)-alkyl-8-oxo-7,8-dihydroguanine (alkyl = propyl, benzyl) that can alternatively pair in a Watson-Crick sense opposite cytosine (C) or as a Hoogsteen pair opposite adenine (A). Cellular delivery with C opposite led to effective targeting of A-containing but not C-containing mRNA sequences in a dual luciferase assay with RNA interference levels that were generally as good as or better than unmodified sequences. The higher activity is ascribed to an inhibitory effect of the alkyl group projecting into the minor groove of double-stranded RNA preventing off-target binding to proteins such as PKR (RNA-activated protein kinase).
小干扰双链 RNA 已被合成，在向导链的核苷酸位置 4、11 和/或 16 处具有一个或多个碱基修饰。该化学修饰碱基是 N(2)- 烷基-8-氧代-7,8-二氢鸟嘌呤（烷基=丙基、苄基），可以在沃森-克里克意义上与胞嘧啶（C）配对，或者与腺嘌呤（A）形成 Hoogsteen 对。在双荧光素酶测定中，与 C 配对的细胞递送导致含有 A 的但不含有 C 的 mRNA 序列有效靶向，其 RNA 干扰水平通常与未修饰序列一样好或更好。更高的活性归因于烷基基团在双链 RNA 的小沟中突出，防止与蛋白质（如 PKR（RNA 激活蛋白激酶））的非靶结合的抑制作用。
