Unmodified short interfering RNAs (siRNAs) are highly potent and effective at directing the selective digestion of specific messenger RNAs inside living cells.  However, the native RNA structure has numerous drawbacks as a therapeutic agent.   For instance, unmodified RNA is sensitive to nucleases, has poor delivery properties and can stimulate immune responses.  While chemical modifications have been described that address these issues, the vast majority of this work has focused on structural changes to the ribose of the component nucleotides.  Modification of the nucleobases can have profound effects on the properties of oligonucleotides, yet this has been a comparatively unexplored route to the modulation of siRNA properties.  Here we report the effects of newly developed base modifications for siRNAs.   Purine derivatives with substituents that project into either the minor groove or the major groove of siRNA are discussed.  These modifications are shown to modulate RNAi potency, binding to off-target proteins and Toll-like receptor mediated immune stimulation.

Controlling siRNA properties with nucleobase modifications

248th National Meeting (2014)

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