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The discovery of RNA interference (RNAi) generated considerable interest in developing short interfering RNAs (siRNAs) for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. | MINIREVIEW Designing highly active siRNAs for therapeutic applications S. Patrick Walton Ming Wu Joseph A. Gredell and Christina Chan Department of ChemicalEngineering and Materials Science Michigan State University East Lansing MI USA Keywords asymmetry chemical modifications design RNAi selection siRNA structural modifications terminalnucleotides therapeutics thermodynamics Correspondence S. Patrick Walton Cellular and Biomolecular Laboratory Department of Chemical Engineering and Materials Science 3249 Engineering Building East Lansing MI 48824-1226 USA Fax 1 517 432 1105 Tel 1 517 432 8733 E-mail spwalton@egr.msu.edu Website http www.egr.msu.edu cbl Received 7 July 2010 revised 16 September 2010 accepted 5 October 2010 doi 10.1111 j.1742-4658.2010.07903.x The discovery of RNA interference RNAi generated considerable interest in developing short interfering RNAs siRNAs for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. As interest in applying RNAi has increased the methods for identifying active siRNA sequences have evolved from focusing on the simplicity of synthesis and purification to identifying preferred target sequences and secondary structures to predicting the thermodynamic stability of the siRNA. As more specific details of the RNAi mechanism have been defined these have been incorporated into more complex siRNA selection algorithms increasing the reliability of selecting active siRNAs against a single target. Ultimately design of the best siRNA therapeutics will require design of the siRNA itself in addition to design of the vehicle and other components necessary for it to function in vivo. In this minireview we summarize the evolution of siRNA selection techniques with a particular focus on one issue of current importance to the
