New Chemically Modified Single-Stranded RNA Turns On RNAi Pathway | Chemical & Engineering News
Volume 90 Issue 36 | p. 58 | Concentrates
Issue Date: September 3, 2012

New Chemically Modified Single-Stranded RNA Turns On RNAi Pathway

Chemical modifications allow single-stranded RNAs to silence genes via RNAi pathway
Department: Science & Technology
News Channels: Biological SCENE
Keywords: RNA interference, gene silencing, huntingtin protein, Huntingdon’s disease, RISC

Chemical modifications allow single-stranded RNAs to silence gene expression via the RNA interference (RNAi) pathway, scientists at Isis Pharmaceuticals, in Carlsbad, Calif., report (Cell, DOI: 10.1016/j.cell.2012.08.014). Conventional small interfering RNAs (siRNAs) are double-stranded and require formulation with lipids for efficient delivery to tissues. Single-stranded RNAs don’t need such lipid formulations, but they have difficulty entering the RNAi pathway. Walt F. Lima, Stanley T. Crooke, and coworkers chemically modified single-stranded RNA so that it interacts directly with Ago2, the enzyme that is responsible for mRNA cleavage in RNAi. Key modifications to the single-stranded siRNA include a 5´-(E)-vinylphosphonate (shown), phosphorothioate linkages between nucleotides, and a mixture of 2´-fluoro, 2´-methoxy, and 2´-methoxyethyl ribonucleotides. The vinylphosphonate, which is conformationally and stereoelectronically similar to natural 5´-phosphates, is necessary for direct loading into Ago2. David R. Corey of the University of Texas Southwestern Medical Center, in Dallas, and coworkers collaborated with the Isis team to use single-stranded siRNAs to inhibit expression of mutant huntingtin protein, which causes Huntington’s disease (Cell, DOI: 10.1016/j.cell.2012.08.002).

 
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