The emerging functional importance of non-coding RNA in regulatory processes provides a major impetus toward the development of tools for selective recognition of RNA sequences. Since many non-coding RNAs fold into double helical motifs, recognition of dsRNA using triplex forming oligonucleotides affords an attractive solution to this problem. Peptide nucleic acids (PNA) offer a stable scaffold capable of modification which can be engineered for strong binding.  To date, polypurine tracts can be recognized with high affinity and selectivity under physiologically relevant conditions using PNA containing Thymidine (T) and 2-aminopyridine (M) bases.  However, binding of pyrimidines remains a challenge and there still exists no general method for the sequence selective recognition of any sequence of dsRNA.<br/> <br/>Our experimental approach aims to discover an extended scaffold capable of spanning the entire Hoogsteen face of the Watson-Crick base pair and hydrogen bonding to both bases. Thus, we aim to use the strong binding that T has for A or M for G to increase affinity when attempting to recognize uracil or cytosine respectively. Using a computational approach, we first seek out reasonable targets that contain the necessary hydrogen-bonding patterns and afford a planar system capable of stacking in a triple helix. Synthesis of new monomers ultimately results in modified PNAs that are tested for binding using isothermal titration calorimetry. This presentation will highlight both design and progress toward intended targets along with studies on PNA-RNA binding.

Design, synthesis, and binding of extended nucleobases in modified peptide nucleic acids for sequence selective recognition of dsRNA

ACS Fall 2021

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