Peptide nucleic acid (PNA) is an artificial nucleic acid having an achiral, peptide-like backbone in place of the sugar-phosphate backbone found in DNA and RNA.  PNA shows tremendous potential for use in biological applications due to its greater binding affinity, selectivity, and strand-invasion capability relative to native nucleic acids, as well as its resistance to degradation by nucleases and proteases.  However, the use of PNA for biological applications has been limited by its poor cell permeability and short circulation lifetime in vivo.  Our research explores the hypothesis that incorporation of negatively charged side chains on the PNA backbone will enable PNA to �electrostatically mimic� DNA and RNA, and thus be compatible with the charge-based delivery technologies that are currently available for native nucleic acids.The enhanced thermodynamic stability of PNA:DNA and PNA:RNA duplexes has been attributed in part to the lack of electrostatic repulsion between the uncharged PNA backbone and negatively charged DNA or RNA backbone.  According to this notion, incorporating negative charge into the PNA backbone would be expected to dramatically decrease binding affinity with DNA and RNA. However, there are no previously reported studies that systematically evaluate this hypothesis. We synthesized PNA strands having negatively or positively charged side chains, then measured their duplex stability with DNA or RNA at varying salt concentrations.  At low salt concentrations, positively charged PNA binds more strongly to DNA and RNA than does negatively charged PNA. However, at medium to high salt concentrations, this trend is reversed, and negatively charged PNA shows higher affinity for DNA and RNA than does positively charged PNA. These results show that charge screening by counterions in solution enables negatively charged side chains to be incorporated into the PNA backbone without reducing duplex stability with DNA and RNA.

Tailoring peptide nucleic acids to electrostatically mimic DNA and RNA

246th National Meeting (2013)

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