Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 25, Issue 17, Pages 4367-4372Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201806293
Keywords
nucleic acids; nucleobases; peptide nucleic acid (PNA); RNA recognition; triple helix
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Funding
- US National Science Foundation (NSF) [CHE-1708761, CHE-1708699]
- NSF [CHE-0922815]
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The development of new RNA-binding ligands is attracting increasing interest in fundamental science and the pharmaceutical industry. The goal of this study was to improve the RNA binding properties of triplex-forming peptide nucleic acids (PNAs) by further increasing the pK(a) of 2-aminopyridine (M). Protonation of M was the key for enabling triplex formation at physiological pH in earlier studies. Substitution on M by an electron-donating 4-methoxy substituent resulted in slight destabilization of the PNA-dsRNA triplex, contrary to the expected stabilization due to more favorable protonation. To explain this unexpected result, the first NMR structural studies were performed on an M-modified PNA-dsRNA triplex which, combined with computational modeling identified unfavorable steric and electrostatic repulsion between the 4-methoxy group of M and the oxygen of the carbonyl group connecting the adjacent nucleobase to PNA backbone. The structural studies also provided insights into hydrogen-bonding interactions that might be responsible for the high affinity and unusual RNA-binding preference of PNAs.
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