Abstract
Developed in the early 1990s, peptide nucleic acid (PNA) has emerged as a promising class of nucleic acid mimic because of its strong binding affinity and sequence selectivity toward DNA and RNA and resistance to enzymatic degradation by proteases and nucleases; however, the main drawbacks, as compared to other classes of oligonucleotides, are water solubility and biocompatibility. Herein we show that installation of a relatively small, hydrophilic (R)-diethylene glycol ("miniPEG", R-MP) unit at the γ-backbone transforms a randomly folded PNA into a right-handed helix. Synthesis of optically pure (R-MP)γPNA monomers is described, which can be accomplished in a few simple steps from a commercially available and relatively cheap Boc-l-serine. Once synthesized, (R-MP)γPNA oligomers are preorganized into a right-handed helix, hybridize to DNA and RNA with greater affinity and sequence selectivity, and are more water soluble and less aggregating than the parental PNA oligomers. The results presented herein have important implications for the future design and application of PNA in biology, biotechnology, and medicine, as well as in other disciplines, including drug discovery and molecular engineering.
Highlights
Peptide nucleic acid (PNA) is a promising class of nucleic acid mimic developed in the last two decades in which the naturally occurring sugar phosphodiester backbone is replaced with N-(2-aminoethyl)glycine units (Chart 1).[1]
We showed that the fully-modified, L-alanine-derived γPNAs (S-AlaγPNAs) can invade mixed-sequence double helical B-form DNA (B-DNA).[81]. Though they are promising as antisense and antigene reagents, S-AlaγPNAs are poorly soluble in water and have a tendency to aggregate, presumably due to the charge-neutral backbone and hydrophobic character of the methyl group at the γ-backbone position
Only the heteroatoms at the periphery of nucleobases are exposed to and interact with the water molecules. This may explain the nonlinear relationship between the number of MP units and the saturating concentrations of PNA oligomers. This suggestion was corroborated by additional experiments (Figure S1, Supplemental Information) which showed that incorporation of a single methyl group instead of MP at the γ-backbone of PNA resulted in nearly 1.2-fold improvement in water solubility, while the reversed trend was observed with additional methyl groups
Summary
Peptide nucleic acid (PNA) is a promising class of nucleic acid mimic developed in the last two decades in which the naturally occurring sugar phosphodiester backbone is replaced with N-(2-aminoethyl)glycine units (Chart 1).[1]. Based on the CD, NMR,[69] and X-ray[73] data which showed that γPNAs derived from Lamino acids adopt a right-handed helix, and that the helix becomes more rigid as more γchiral units are added in the backbone, one would expect a fully-modified PNA5 to hybridize to DNA and RNA targets with greater sequence selectivity than PNA1.
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