Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, California 95616, USA.
J Am Chem Soc. 2011 Jun 22;133(24):9200-3. doi: 10.1021/ja202492e. Epub 2011 Jun 1.
Immune stimulation is a significant hurdle in the development of effective and safe RNA interference therapeutics. Here, we address this problem in the context of a mimic of microRNA-122 by employing novel nucleobase and known 2'-ribose modifications. The nucleobase modifications are analogues of adenosine and guanosine that contain cyclopentyl and propyl minor-groove projections. Via a site-by-site chemical modification analysis, we identify several immunostimulatory 'hot spots' within the miRNA guide strand at which single base modifications significantly reduce immune stimulation. A duplex containing one base modification on each strand proved to be most effective in preventing immune stimulation.
免疫刺激是开发有效和安全的 RNA 干扰治疗方法的重大障碍。在这里，我们通过采用新型核苷碱基和已知的 2'-核糖修饰来解决这个问题。核苷碱基修饰是腺苷和鸟苷的类似物，含有环戊基和丙基小沟突起。通过逐个碱基化学修饰分析，我们在 miRNA 引导链上确定了几个免疫刺激性“热点”，其中单个碱基修饰可显著降低免疫刺激。在每条链上进行一个碱基修饰的双链体被证明是预防免疫刺激最有效的。
