Nucleobase and ribose modifications control immunostimulation by a microRNA-122-mimetic RNA

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Biomimetic Materials / adverse effects*
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry*
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Gene Knockdown Techniques
  • Immune System / drug effects*
  • Immune System / metabolism
  • Mice
  • MicroRNAs / genetics*
  • RNA, Double-Stranded / adverse effects*
  • RNA, Double-Stranded / chemical synthesis
  • RNA, Double-Stranded / chemistry*
  • RNA, Double-Stranded / genetics
  • Ribose / chemistry*


  • Cytokines
  • MicroRNAs
  • Mirn122 microRNA, mouse
  • RNA, Double-Stranded
  • Ribose