Nucleic Acid Backbone Structure Variations: Peptide Nucleic Acids


Synthetic analogues and mimics of the natural genetic material deoxyribonucleic acid (DNA) are potential gene therapeutic (antisense or antigene) drugs. One of these mimics, peptide nucleic acids (PNAs), are chemically closer to peptides and proteins than to DNA, but nonetheless have retained many of the structural properties of DNA. These molecules have found applications as probes in genetic diagnostics and are also being developed into antisense (ribonucleic acid (RNA) interference) gene therapeutic drugs, targeting selected genes through sequence‐specific recognition of (messenger or micro)RNA, and in the future also antigene applications targeting the double‐stranded DNA of the genes themselves leading to gene silencing or guiding specific gene repair. Finally, the special chemical and structural properties of PNA suggest that these or similar molecules might have played a role in the prebiotic origin of life (on Earth) and also could be interesting components of possible artificial life.

Key Concepts:

  • Peptide nucleic acid (PNA) is a DNA mimic in which the backbone consists of a charge neutral pseudo peptide.

  • Peptide nucleic acids can be designed to bind sequence selectively to duplex DNA and thus may function as ‘antigene’ drugs.

  • A range of chemical structures can mimic various functions of our genetic material, the DNA.

  • Chemical modifications and structural mimics of DNA are useful as genetic diagnostic probes and are being developed into gene therapeutic drugs.

  • RNA interference drug sequences specifically bind to cellular (messenger or micro)‐RNA and interfere with (inhibit) their function.

  • Prebiotic origin of life could have involved peptide nucleic acid molecules as predecessors of RNA.

Keywords: peptide nucleic acid (PNA); antisense; genetic diagnostics; gene therapeutic drugs; origin of life

Figure 1.

Chemical structures of peptide nucleic acid (PNA) in comparison with DNA and a natural peptide. The resemblance of PNA to both peptides and DNA is apparent. However, chemically, PNA is synthesised and ‘behaves’ like a peptide. ‘B’ signifies a nucleobase: adenine (A), cytosine (C), guanine (G) or thymine (T), and ‘R’ is an amino acid side‐chain.

Figure 2.

Chemical structures of the natural nucleobases adenine (A), cytosine (C), guanine (G) and thymine (T), forming A–T and G–C Watson–Crick base pairs.

Figure 3.

Binding modes of peptide nucleic acid (PNA) when targeting double‐stranded DNA. At present, most studies have been concerned with the extremely stable triplex invasion complexes. The ladder represents a schematic DNA double helix and PNA oligomers are shown in bold. The triplex (a) and triplex invasion complexes (b) require a homopurine target and thus a homopyrimidine PNA. Because the double duplex complex (d) requires two sequence‐complementary PNAs that would normally bind to each other, these PNAs have to be constructed with ‘pseudo‐complementary’ bases (Lohse et al., ). The duplex invasion complex (c) can, in principle, form with any sequence PNA. However, for unmodified PNA the formed PNA–DNA complexes are not very stable, but the complex can be significantly stabilized using gamma‐PNAs, having a substituent (e.g. R=–CH3 or –CH2(CH2CH2O)2CH3) in the γ‐position in the backbone (see Figure , ‘R’ in PNA) (e) the nucleobases in PNA–DNA–PNA triple helices are arranged in base triplets via (A‐T and G‐C) Watson‐Crick and (A‐T and GC+ (protonated C)) Hoogsteen base pairing. PNA is shown in red, DNA in black. Pseodoiso C is a cytosine analogue that does not require protonation) (Sahu et al., ).

Figure 4.

Schematic drawing of the principle of antisense inhibition of translation. Following the ‘central dogma’, the DNA of a gene is transcribed into a mRNA copy, which is subsequently translated into the functional gene product, a protein. The antisense reagent interferes with this process by binding to a short region (15–20 nucleotides) of the target mRNA, thereby causing degradation of the RNA (e.g. via ribonuclease H), or by physically blocking the ribosomal translation process, and thereby inducing nonsense‐mediated mRNA decay.

Figure 5.

Chemical structures of examples of DNA analogues and mimics of interest as gene therapeutic drugs and as probes in molecular biology and genetic diagnostics. PNA, peptide nucleic acid (R=H for original PNA); PPNA, phosphono‐PNA; 2′‐ODN (oligodeoxynucleiotide), 2′‐substituted DNA (the substituent may be methoxy); DNG, deoxynucleic guanidine; LNA, locked nucleic acid and HNA, hexose nucleic acid. ‘B’ signifies a nucleobase: adenine (A), cytosine (C), guanine (G) or thymine (T).



Ahn TS, Jeong D, Son MW et al. (2014) The BRAF mutation is associated with the prognosis in colorectal cancer. Journal of Cancer Research and Clinical Oncology [Epub ahead of print] PMID: 24942334.

Böhler C, Nielsen PE and Orgel LE (1995) Template switching between PNA and RNA oligonucleotides. Nature 376: 578–581.

Chin JY, Kuan JY, Lonkar PS et al. (2008) Correction of a splice‐site mutation in the beta‐globin gene stimulated by triplex‐forming peptide nucleic acids. Proceedings of the National Academy of Sciences of the United States of America 105: 13514–13519.

Desai AN and Jere A (2012) Next‐generation sequencing: ready for the clinics? Clinical Genetics 81: 503–510.

Eriksson M and Nielsen PE (1996) PNA–nucleic acid complexes. Structure, stability and dynamics. Quarterly Reviews of Biophysics 29: 369–394.

Faruqi AF, Egholm M and Glazer PM (1998) Peptide nucleic acid‐targeted mutagenesis of a chromosomal gene in mouse cells. Proceedings of the National Academy of Sciences of the United States of America 95(4): 1398–1403.

Frieden M and Ørum H (2008) Locked nucleic acid holds promise in the treatment of cancer. Current Pharmaceutical Design 14: 1138–1142.

Geller BL (2005) Antibacterial antisense. Current Opinion in Molecular Therapeutics 7: 109–113.

Ghosal A and Nielsen PE (2012) Potent antibacterial antisense peptide‐peptide nucleic acid conjugates against Pseudomonas aeruginosa. Nucleic Acid Therapy 22: 323–334.

Good L, Awasthi SK, Dryselius R, Larsson O and Nielsen PE (2001) Bactericidal antisense effects of peptide‐PNA conjugates. Nature Biotechnology 19: 360–364.

Iyer RP, Roland A, Zhou W and Ghosh K (1999) Modified oligonucleotides – synthesis properties and applications. Current Opinion in Molecular Therapeutics 1: 344–358.

Lohse J, Dahl O and Nielsen PE (1999) Double duplex invasion by peptide nucleic acid: a general principle for sequence‐specific targeting of double‐stranded DNA. Proceedings of the National Academy of Sciences of the United States of America 96: 11804–11808.

Lonkar P, Kim KH and Kuan JY (2009) Targeted correction of a thalassemia‐associated β‐globin mutation induced by pseudo‐complementary peptide nucleic acids. Nucleic Acids Research 37: 3635–3644.

Nelson KE, Levy M and Miller SL (2000) Peptide nucleic acids rather than RNA may have been the first genetic material. Proceedings of the National Academy of Sciences of the United States of America 97: 3868–3871.

Nielsen PE (1999) Peptide nucleic acid. A molecule with two identities. Account of Chemical Research 32: 624–630.

Nielsen PE (2004) Peptide Nucleic Acids, Protocols and Applications. Norfolk: Horizon Bioscience.

Nielsen PE (2008) A new molecule of life? Scientific American 299: 64–71.

Nielsen PE, Egholm M, Berg RH and Buchardt O (1991) Sequence selective recognition of DNA by strand displacement with a thymine‐substituted polyamide. Science 254: 1497–1500.

Orgel LE (2004) Prebiotic chemistry and the origin of the RNA world. Critical Reviews in Biochemistry and Molecular Biology 39: 99–123.

Sahu B, Sacui I, Rapireddy S et al. (2011) Synthesis and characterization of conformationally preorganized, (R)‐diethyleneglycol‐containing γ‐peptide nucleic acids with superior hybridization properties and water solubility. Journal of Organic Chemistry 76: 5614–5627.

Sazani P, Kang SH and Maier MA (2001) Nuclear antisense effects of neutral, anionic and cationic oligonucleotide analogs. Nucleic Acids Research 29: 3965–3974.

Shendure J and Ji H (2008) Next‐generation DNA sequencing. Nature Biotechnology 26: 1135–1145.

Søgaard M, Hansen DS, Fiandaca MJ, Stender H and Schønheyder HC (2007) Peptide nucleic acid fluorescence in situ hybridization for rapid detection of klebsiella pneumoniae from positive blood cultures. Journal of Medical Microbiology 56: 914–917.

Tan XX, Actor JK and Chen Y (2005) Peptide nucleic acid antisense oligomer as a therapeutic strategy against bacterial infection: proof of principle using mouse intraperitoneal infection. Antimicrobial Agents and Chemotherapy 49: 3203–3207.

Wu B, Li Y, Morcos PA et al. (2009) Octa‐guanidine morpholino restores dystrophin expression in cardiac and skeletal muscles and ameliorates pathology in dystrophic mdx mice. Molecular Therapy 17: 864–871.

Yin H, Lu Q and Wood M (2008) Effective exon skipping and restoration of dystrophin expression by peptide nucleic acid antisense oligonucleotides in Mdx mice. Molecular Therapy 16: 38–45.

Yokota T, Lu QL and Partridge T (2009) Efficacy of systemic morpholino exon‐skipping in duchenne dystrophy dogs. Annals of Neurology 65: 667–676.

Further Reading

Ivanova GD, Arzumanov A and Abes R (2008) Improved cell‐penetrating peptide‐PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle. Nucleic Acids Research 36: 6418–6428.

Katada H and Komiyama M (2009) Artificial restriction DNA cutters as new tools for gene manipulation. ChemBioChem 10: 1279–1288.

Pianowski ZL and Winssinger N (2008) Nucleic acid encoding to program self‐assembly in chemical biology. Chemical Society Reviews 37: 1330–1336.

Pouchain D, Diaz‐Mochon JJ, Bialy L and Bradley M (2007) A 10 000 member PNA‐encoded peptide library for profiling tyrosine kinases. ACS Chemical Biology 2: 810–818.

Röglin L, Ahmadian MR and Seitz O (2007) DNA‐controlled reversible switching of peptide conformation and bioactivity. Angewandte Chemie‐International Edition 46: 2704–2707.

Wojciechowski F and Hudson RH (2007) Nucleobase modifications in peptide nucleic acids. Current Topics in Medicinal Chemistry 7: 667–679.

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Nielsen, Peter E(Nov 2014) Nucleic Acid Backbone Structure Variations: Peptide Nucleic Acids. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003130.pub3]