Discovery of RNA interference has reinvigorated interest in chemical modifications of RNA for in vivo applications. Our current work is focused on the development of novel nonionic analogues of RNA that have the phosphodiesters replaced by amide linkages.We hypothesize that the reduced negative charge and the hydrophobic nature of such modifications will not only increase the enzymatic stability but also have the potential to optimize potency, cellular uptake, and pharmacokinetics of small interfering RNAs. A further advantage of amide modifications in RNA is that they can be prepared using relatively straightforward peptide type couplings. This presentation will discuss synthesis and biophysical properties of amide-modified RNA analogues. The results obtained using osmotic stress, NMR spectroscopy and x-ray crystallography suggest interesting insights into how the formally hydrophobic modifications interact with hydration of RNA (1). Preliminary results on biological activity show that amides are well tolerated in both strands of modified siRNAs. The implications of these studies for practical applications of modified RNA analogues in RNA interference will be discussed.1. Selvam, C.; Thomas, S.; Abbott, J.; Kennedy, S. D.; Rozners, E. Amides Are Excellent Mimics of Phosphate Linkages in RNA Angew. Chem. Int. Ed. 2011  , 50, 2068-2070.

Synthesis and properties of amide-modified RNA for applications in RNA interference

247th National Meeting (2014)

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