Design and Synthesis of Hoogsteen-Binding Peptide Nucleic Acid Monomers with Extended Linkers for Triple Helical U-A Recognition in RNA

RNA provides many functions within biological systems. For example, noncoding RNA (ncRNA), a form of RNA that is not part of transcription or translation, serves a variety of unique roles, such as catalysis or gene regulation. ncRNA generally forms double helical motifs that are ripe for molecular recognition. Sequence selective recognition of double helical RNA (dhRNA) can be achieved using Peptide Nucleic Acids (PNA) through triple helical formation by Hoogsteen hydrogen bonding of PNA nucleobases in the major groove of dhRNA. However, strong, and selective recognition is typically limited to polypurine strands and pyrimidine recognition remains an unsolved problem. A promising solution uses extended nucleobases to reach across the Hoogsteen face of the RNA base pair, bypassing the pyrimidine, and binding with the distal purine. Using this strategy, we designed and synthesized new extended nucleobases to help uncover the ideal linker length and heterocyclic substitution for optimal molecular recognition