news of the week AUGUST 12, 2013 EDITED BY WILLIAM G. SCHULZ & EMILY BONES
a repeat sequence in an RNA molecule folded over in the shape of a hairpin. It’s not clear if the technique will work for RNAs folded into more elaborate threedimensional shapes, but Disney says he believes his team will be able to demonstrate that. DRUG DISCOVERY: Reactions “The approach is likely general and could make it possible to show if a drug be applied to a wide range of disease-as“The approach is likely candidate hits its RNA target sociated RNAs,” he says. Follow-up plans general and could also include enhancing the selectivity of be applied to a wide the small-molecule/RNA reactions and range of diseaseRUG RESEARCHERS, always on the lookout for identifying RNA target interactions in associated RNAs.” new targets, are increasingly setting their sights animal models of disease. —MATTHEW D. DISNEY, SCRIPPS on ribonucleic acids (RNAs). These biological Chemical biologist Victoria J. DeRose RESEARCH INSTITUTE FLORIDA molecules control many essential cellular functions and coworkers at the University of Oreand are associated with some diseases. gon have devised a complementary methBut proving that drug candidates hit the intended od that adds a reactive azide group to an RNA-binding RNA targets has turned out to be difficult. RNA, in small molecule. They demonstrated the approach fact, has earned a reputation as being “undruggable” with the platinum-based cancer drug picoplatin. The with small molecules because small-molecule/RNA azide modification enables the team to use a click interactions are difficult chemistry reaction—in to detect and characterthis case a cycloaddition ize. Now, however, two between an azide and techniques make it posan alkyne—to attach sible for the first time to an alkyne-containing CUGCUGCUGCUGCUG CUGCUGCUGCUGCUG detect such interactions fluorescent marker to GUCGUCGUCGUCGUC GUCGUCGUCGUCGUC in cells. the azide-derivatized In one approach, drug after it has bound Cellular RNA RNA target of postdoc Lirui Guan to its RNA target (J. Am. small molecule and chemistry profesChem. Soc. 2013, DOI: sor Matthew D. Disney 10.1021/ja402453k). They BONDING & CAPTURE In the Scripps of Scripps Research are then able to detect technique, a small molecule (purple) that targets a Institute Florida added the drug-bound RNA cytosine-uridine-guanine (CUG) repeat sequence in a chlorambucil reaccomplex by monitoring disease-related RNA is derivatized with a reactive tive group and a biotin its fluorescence both in group (blue) and a biotin afnity tag (green). After affinity-purification tag vitro and in treated cells. binding, the drug covalently bonds to RNA. The to 2H-4, a small molDeRose and coworkcombination is isolated via streptavidin (yellow) ecule (Angew. Chem. Int. ers note that variations binding to biotin, and the RNA is then identified. Ed. 2013, DOI: 10.1002/ on this approach could anie.201301639). It eventually be developed targets a repeating cytosine-uridine-guanine pattern to isolate, purify, and identify drug-bound RNA for in mRNA associated with myotonic dystrophy, a comsequencing, proteomics, or structure-function studies. mon type of muscular dystrophy. In live cells, 2H-4/ Efforts to use click chemistry “to isolate and quantify chlorambucil/biotin bound to and then covalently Pt-bound species are currently under way in our laborabonded to the target sequence. The biotin made it tory,” the researchers say. possible to use beads coated with streptavidin, which “RNA is still an underutilized target because not binds biotin, to isolate and characterize the resulting much is known about how small molecules interact small-molecule/RNA complex, enabling the scientists with various RNA secondary and tertiary structure to verify that the molecule had hit the desired RNA motifs,” says Christine S. Chow of Wayne State Unitarget. versity, who is a specialist in small-molecule/nucleic As a bonus, the covalent bonding interaction boostacid interactions. “Probing small-molecule interaced 2H-4’s ability to repair cellular defects associated tions with cellular RNA targets has not been achieved with the disease 2,500 times relative to the efficacy of before with designed and selected compounds that unmodified 2H-4. target specific RNA structural motifs,” she notes.— Guan and Disney demonstrated their technique on STU BORMAN
PROBING DRUG-RNA INTERACTIONS
ADAPTED FROM ANGEW. CHEM. INT. ED.
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