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J Am Chem Soc. 2011 Jun 22;133(24):9200-3. doi: 10.1021/ja202492e. Epub 2011 Jun 1.

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

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  • 1Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, California 95616, USA.


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.

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