Gene Silencing By Design | November 18, 2013 Issue - Vol. 91 Issue 46 | Chemical & Engineering News
Volume 91 Issue 46 | p. 8 | News of The Week
Issue Date: November 18, 2013

Gene Silencing By Design

Drug Discovery: Tweaking short interfering RNAs improves their ability to turn off bad genes
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE, Analytical SCENE, JACS In C&EN
Keywords: Argonaute, RNAi, RNA interference, siRNA, short interfering RNA, structure-based design
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A nucleotide modification (red star) improves the potency of siRNA at targeting a specific messenger RNA for destruction by Argonaute (yellow oval).
Credit: Courtesy of Peter Beal
Schematic shows how a nucleotide modification (red star) improves the potency of siRNA at targeting a specific mRNA for destruction by Argonaute (yellow oval).
 
A nucleotide modification (red star) improves the potency of siRNA at targeting a specific messenger RNA for destruction by Argonaute (yellow oval).
Credit: Courtesy of Peter Beal

When new protein structures are reported, it’s often claimed they could lead to the design of therapeutic agents that interact with the proteins more effectively. A new study on short interfering RNAs (siRNAs) actually demonstrates such a result.

Last year, two research groups determined crystal structures of the human version of Argonaute—a protein in the RNA interference (RNAi) pathway that cells use to turn off target genes. siRNAs activate RNAi in cells by binding to messenger RNAs for targeted genes and marking them for destruction by Argonaute.

siRNAs could thus be used therapeutically to turn off problematic genes related to various diseases. But designing siRNA drugs isn’t easy because they don’t readily enter cells, are broken down and excreted quickly, produce immune reactions, and cause side effects by inhibiting off-target genes. Nevertheless, several chemically modified siRNA drug candidates have entered human clinical trials.

Dean J. Tantillo, Peter A. Beal, and coworkers at the University of California, Davis, have now modified siRNAs in a new way—by using Argonaute’s crystal structures for the first time as a jumping-off point for structure-based siRNA redesign (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja4079754).

siRNAs must bind Argonaute to initiate gene silencing, and the way the siRNAs bind affects potency. The UC Davis researchers used target docking simulations and their own chemical intuition to find siRNA modifications that improve potency by changing the way siRNAs bind Argonaute. Higher potency enables lower doses of a drug treatment, which tends to reduce side effects.

The group’s best redesigned siRNA—in which the terminal nucleotide is replaced with an analog—is nearly 20% more potent than the natural version in lab tests. The increase is only modest but improvable, the researchers believe. “New analogs discovered using our approach that enhance RNAi activity will be patented,” Beal says.

The work should inspire chemical modifications “that address some of the shortcomings of siRNA as potential therapeutics,” comments siRNA-modification expert Masad J. Damha of McGill University.

 
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ISSN 0009-2347
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