NEWS OF THE WEEK
industrially produced trans fat in foods,” says Dennis M. Keefe, director of FDA’s Office of Food Additive Safety. Consumers began avoiding trans fat more than a decade ago on the advice of medical experts, and in response, manufacturers dramatically reduced the amount of partially hydrogenated oils used in processed foods. But the artery-clogging fats can still be found in many products, including frozen pizza, microwave popcorn, and cake frosting. Public health groups welcome FDA’s move, emphasizing that artificial trans fat is not safe and not necessary. Food manufacturers, on the other hand, are concerned about the possibility of FDA using the same regulatory approach on other food ingredients that are currently under scrutiny, such as sugars, sodium, and caffeine. “I would certainly expect FDA to use the approach with respect to other ingredients that are considered safe based on industry self-assessments,” says Mitchell Cheeseman, who led FDA’s Office of Food Additive Safety before joining the law firm Steptoe & Johnson in 2011. Cheeseman also warns that FDA’s action could trigger lawsuits against food manufacturers that have known about the dangers of partially hydrogenated oils for many years but failed to warn consumers. FDA is accepting comments on its decision until Jan. 7, 2014.—BRITT ERICKSON
GOOD-BYE, TRANS FAT REGULATION: FDA effort to eliminate partially hydrogenated oils draws mixed response UBLIC HEALTH GROUPS hail the Food & Drug
P SHUTTERSTOCK
FDA is taking action to eliminate partially hydrogenated oils in processed foods.
Administration’s recent move to eliminate partially hydrogenated oils—the biggest dietary source of artificial trans fat—from processed foods. But some manufacturers worry that FDA might extend the approach to other food ingredients that concern health activists but have been deemed safe by industry. FDA announced earlier this month that partially hydrogenated oils will no longer be considered “generally recognized as safe,” citing risks of heart disease and evidence that alternative ingredients exist. If FDA finalizes that decision, the food industry will, for the first time, have to show that partially hydrogenated oils are safe in order to use them in processed foods. The agency has solid evidence associating the consumption of such oils with an increased risk of heart disease, so “it could, in effect, mean the end of artificial,
GENE SILENCING BY DESIGN
5´ 3´
3´ 5´ siRNA
+
DRUG DISCOVERY: Tweaking short
interfering RNAs improves their ability to turn off bad genes
W
HEN 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 Target mRNA activate RNAi in cells by binding Target binding to messenger RNAs for targeted genes and marking them for destruction by Argonaute. siRNAs could thus be used therapeutically to turn off probCleavage lematic genes related to various diseases. But designing siRNA CEN.ACS.ORG
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COURTESY OF PETER BEAL
A nucleotide modification (red star) improves the potency of siRNA at targeting a specific messenger RNA for destruction by Argonaute (yellow oval).
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.—STU BORMAN
NOVEMBER 18, 2013
