Sequence‐Specific Installation of Aryl Groups in RNA via DNA‐Catalyst Conjugates

Abstract Installing functional groups at specific sites in existing RNA molecules remains a challenge for modification, labeling, and therapeutic strategies. Here, we describe the use of DNA oligonucleotides carrying a catalytic amine group to effect the aqueous S N Ar arylation of 2′‐OH groups at sequence‐complementary sites in RNAs. Chloro‐pyrimidine electrophiles are shown to react with amino‐DNA conjugates, resulting in a proposed transient ammonium aryl intermediate that can react with RNA near the DNA binding site, delivering the heterocycle to the RNA in high yields. In a test of utility, we construct an aryl electrophile carrying an azide group, and apply this strategy to fluorescently label messenger RNAs locally at the polyA tail. We also employ the approach to direct in vitro arylation in the coding region of a messenger RNA, knocking down protein expression selectively in the presence of another coding RNA. This sequence‐directed catalytic strategy enables multiple applications in RNA labeling and modification.