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Sequence Selective Recognition of Double Helical RNA Using Nucleobase‐Modified PNA

The important role that non‐coding RNA plays in cell biology makes it an attractive target for molecular recognition. The surface of an RNA helix is relatively uniform, dominated by negatively charged phosphates and presents little opportunity for the traditional shape selective molecular recognition. We envisioned that a hydrogen bond mediated major groove triple helix formation could provide the most straightforward sequence selective recognition of double helical RNA. Using isothermal titration calorimetry we show that peptide nucleic acids, as short as six nucleobases, bind very strongly (Ka > 107) and sequence selectively to polypurine tract of double helical RNA. The data suggest that the binding mode is a sequence selective triple helix formation. Although RNA does not have long polypurine tracts, it is common to find stretches of seven and more purines interrupted by one or two pyrimidines in microRNAs and ribosomal RNAs. We found that such pyrimidine interruptions in the polypurine tracts of biologically relevant RNAs can be recognized in a sequence specific manner using nucleobase‐modified PNA under physiologically relevant conditions. Our results have implications for development of biochemical probes to study function of non‐coding RNAs and design of novel therapeutic approaches based on sequence selective inhibition of microRNAs. Supported by NIH R01 GM071461