380584 Determinants of siRNA Function

Wednesday, November 19, 2014
Galleria Exhibit Hall (Hilton Atlanta)
Phillip Angart and S. Patrick Walton, Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI

The use of biological molecules as therapeutics, biologics, is a rapidly expanding area of pharmaceutical research because of its high specificity and low toxicity. Biologics often utilize native cellular mechanisms to amplify their activity while producing minimal perturbation of cellular function. Short interfering RNAs (siRNAs) are class of biologics that are able to enact gene silencing in conjunction with the native eukaryotic regulatory pathway called RNA interference (RNAi). The canonical siRNA is double-stranded with 19 central bases and 2 nucleotide 3’ overhangs. The RNAi pathway recognizes the siRNA structure and then removes one of the RNA strands to form an active complex called RISC, which finds its target through the now free base pairs of the remaining siRNA strand. While the recognition of the siRNA by the RNAi pathway is largely structurally based, siRNA activity can vary greatly with siRNA sequence. Our previous work identified that the 5’ terminal nucleotide sequence and the relative terminal hybridization stability of the siRNA were both independent and strongly predictive of siRNA activity. In this presentation, we will discuss how these two characteristics correlate with functional molecular events within the RNAi pathway as well as their impact on siRNA design.

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