Modulation of Nucleic Acid Information Processing by PNAs

Potential Use in Anti-Viral Therapeutics
  • Lionel Bastide
  • Bernard Lebleu
  • Ian Robbins
Part of the Medical Intelligence Unit book series (MIUN)


The capacity of short PNAs to selectively bind specifically-targeted nucleic acid sequences, either by Watson-Crick base pairing or by triple-helix formation involving Hoogstein bonding, confers on them an enormous potential to interfere with nucleic acid information processing. Their incapacity of forming a suitable substrate for RNase H has often been considered a major limiting factor to their capacity to regulate gene expression. It is now clear, however, that judicious targeting can lead to the disruption of specific and crucial steps of nucleic acid information processing. This is particularly true of many of the mechanisms that are specific to viruses.


Human Immunodeficiency Virus Internal Ribosome Entry Site Triple Helix Peptide Nucleic Acid Nucleic Acid Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nielsen PE, Egholm M, Berg RH et al. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991; 254(5037):1497–1500.PubMedCrossRefGoogle Scholar
  2. 2.
    Egholm M, Buchardt O, Christensen L et al. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature 1993; 365(6446):566–568.PubMedCrossRefGoogle Scholar
  3. 3.
    Demidov VV, Potaman VN, Frank-Kamenetskii MD et al. Stability of peptide nucleic acids in human serum and cellular extracts. Biochem Pharmacol 1994; 48(6):1310–1313.PubMedCrossRefGoogle Scholar
  4. 4.
    Hanvey JC, Peffer NJ, Bisi JE et al. Antisense and antigene properties of peptide nucleic acids. Science 1992; 258(5087):1481–1485.PubMedCrossRefGoogle Scholar
  5. 5.
    Peffer NJ, Hanvey JC, Bisi JE et al. Strand-invasion of duplex DNA by peptide nucleic acid oligomers. Proc Natl Acad Sci USA 1993; 90(22):10648–10652.PubMedCrossRefGoogle Scholar
  6. 6.
    Knudsen H, Nielsen PE. Antisense properties of duplex-and triplex-forming PNAs. Nucleic Acids Res 1996; 24(3):494–500.PubMedCrossRefGoogle Scholar
  7. 7.
    Boffa LC, Scarfi S, Mariani MR et al. Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res 2000; 60(8):2258–2262.PubMedGoogle Scholar
  8. 8.
    Zhang X, Simmons CG, Corey DR. Liver cell specific targeting of peptide nucleic acid oligomers. Bioorg Med Chem Lett 2001; 11(10):1269–1272, (eng).PubMedCrossRefGoogle Scholar
  9. 9.
    Cutrona G, Carpaneto EM, Ulivi M et al. Effects in live cells of a c-myc anti-gene PNA linked to a nuclear localization signal. Nat Biotechnol 2000; 18(3):300–303.PubMedCrossRefGoogle Scholar
  10. 10.
    Pooga M, Soomets U, Hallbrink M et al. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol 1998; 16(9):857–861.PubMedCrossRefGoogle Scholar
  11. 11.
    Villa R, Folini M, Lualdi S et al. Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells. FEES Lett 2000; 473(2):241–248.CrossRefGoogle Scholar
  12. 12.
    Zamaratski E, Pradeepkumar PI, Chattopadhyaya J. A critical survey of the structurefunction of the antisense oligo/RNA heteroduplex as substrate for RNase H. J Biochem Biophys Methods 2001; 48(3):189–208.PubMedCrossRefGoogle Scholar
  13. 13.
    Bielinsky AK, Gerbi SA. Where it all starts: Eukaryotic origins of DNA replication. J Cell Sci 2001; H4 (Pt 4):643–651.Google Scholar
  14. 14.
    Dvir A, Conaway JW, Conaway RC. Mechanism of transcription initiation and promoter escape by RNA polymerase II. Curr Opin Genet Dev 2001; 11(2):209–214.PubMedCrossRefGoogle Scholar
  15. 15.
    Kozak M. Initiation of translation in prokaryotes and eukaryotes. Gene 1999; 234(2):187–208.PubMedCrossRefGoogle Scholar
  16. 16.
    Edwards AM, Bochkarev A, Frappier L. Origin DNA-binding proteins. Curr Opin Struct Biol 1998; 8(1):49–53.PubMedCrossRefGoogle Scholar
  17. 17.
    Kurg R, Langel U, Ustav M. Inhibition of the bovine papillomavirus E2 protein activity by peptide nucleic acid. Virus Res 2000; 66(1):39–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Birg F, Praseuth D, Zerial A et al. Inhibition of simian virus 40 DNA replication in CV-1 cells by an oligodeoxynucleotide covalently linked to an intercalating agent. Nucleic Acids Res 1990; 18(10):2901–2908.PubMedCrossRefGoogle Scholar
  19. 19.
    Praseuth D, Grigoriev M, Guieysse A L et al. Peptide nucleic acids directed to the promoter of the alpha-chain of the interleukin-2 receptor. Biochim Biophys Acta 1996; 1309(3):226–238.PubMedGoogle Scholar
  20. 20.
    Vickers TA, Griffith MC, Ramasamy K et al. Inhibition of NF-kappa B specific transcriptional activation by PNA strand invasion. Nucleic Acids Res 1995; 23(15):3003–3008.PubMedCrossRefGoogle Scholar
  21. 21.
    Duval-Valentin G, Thuong NT, Helene C. Specific inhibition of transcription by triple helix-forming oligonucleotides. Proc Natl Acad Sci USA 1992; 89(2):504–508, (eng).PubMedCrossRefGoogle Scholar
  22. 22.
    Mologni L, Marchesi E, Nielsen PE et al. Inhibition of promyelocytic leukemia (PML)/retinoic acid receptor-alpha and PML expression in acute promyelocytic leukemia cells by anti-PML peptide nucleic acid. Cancer Res 2001; 61(14):5468–5473.PubMedGoogle Scholar
  23. 23.
    Mologni L, leCoutre P, Nielsen PE et al. Additive antisense effects of different PNAs on the in vitro translation of the PML/RARalpha gene. Nucleic Acids Res 1998; 26(8):1934–1938.PubMedCrossRefGoogle Scholar
  24. 24.
    Doyle DF, Braasch DA, Simmons CG et al. Inhibition of gene expression inside cells by peptide nucleic acids: Effect of mRNA target sequence, mismatched bases, and PNA length. Biochemistry 2001; 40(1):53–64.PubMedCrossRefGoogle Scholar
  25. 25.
    Nielsen PE, Egholm M, Berg RH et al. Peptide nucleic acids (PNAs): Potential antisense and anti-gene agents. Anticancer Drug Des 1993; 8(1):53–63.PubMedGoogle Scholar
  26. 26.
    Taylor RW, Chinnery PF, Turnbull DM et al. Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet 1997; 15(2):212–215.PubMedCrossRefGoogle Scholar
  27. 27.
    Muratovska A, Lightowlers RN, Taylor RW et al. Targeting peptide nucleic acid (PNA) to diagramers mitochondria within cells by conjugation to lipophilic cations: Implications for mitochondrial DNA replication, expression and disease. Nucleic Acids Res 2001; 29(9):1852–1863.PubMedCrossRefGoogle Scholar
  28. 28.
    Nielsen PE, Egholm M, Buchardt O. Sequence-specific transcription arrest by peptide nucleic acid bound to the DNA template strand. Gene 1994; 149(1):139–145, (eng).PubMedCrossRefGoogle Scholar
  29. 29.
    Boffa LC, Morris PL, Carpaneto EM et al. Invasion of the GAG triplet repeats by a complementary peptide nucleic acid inhibits transcription of the androgen receptor and TATA-binding protein genes and correlates with refolding of an active nucleosome containing a unique AR gene sequence. J Biol Chem 1996; 271(22):13228–13233.PubMedCrossRefGoogle Scholar
  30. 30.
    Gee JE, Robbins I, van der Laan AC et al. Assessment of high-affinity hybridization, RNase H cleavage, and covalent linkage in translation arrest by antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 1998; 8(2):103–111, (eng).PubMedGoogle Scholar
  31. 31.
    Bias N, Dheur S, Nielsen PE et al. Antisense PNA tridecamers targeted to the coding region of Ha-ras mRNA arrest polypeptide chain elongation. J Mol Biol 1999; 294(2):403–416.CrossRefGoogle Scholar
  32. 32.
    Alberts BM. The DNA enzymology of protein machines. Cold Spring Harb Symp Quant Biol 1984; 49:1–12.PubMedGoogle Scholar
  33. 33.
    Lohman TM, Bjornson KP. Mechanisms of helicase-catalyzed DNA unwinding. Annu Rev Biochem 1996; 65:169–214.PubMedCrossRefGoogle Scholar
  34. 34.
    Kopel V, Pozner A, Baran N et al. Unwinding of the third strand of a DNA triple helix, a novel activity of the SV40 large T-antigen helicase. Nucleic Acids Res 1996; 24(2):330–335.PubMedCrossRefGoogle Scholar
  35. 35.
    Maine IP, Kodadek T. Efficient unwinding of triplex DNA by a DNA helicase. Biochem Biophys Res Commun 1994; 204(3):1119–1124.PubMedCrossRefGoogle Scholar
  36. 36.
    Bastide L, Boehmer PE, Villani G et al. Inhibition of a DNA-helicase by peptide nucleic acids. Nucleic Acids Res 1999; 27(2):551–554.PubMedCrossRefGoogle Scholar
  37. 37.
    Boehmer PE, Lehman IR. Herpes simplex virus DNA replication. Annu Rev Biochem 1997; 66:347–384.PubMedCrossRefGoogle Scholar
  38. 38.
    Tackett AJ, Wei L. Cameron C E et al. Unwinding of nucleic acids by HCV NS3 helicase is sensitive to the structure of the duplex. Nucleic Acids Res 2001; 29(2):565–572.PubMedCrossRefGoogle Scholar
  39. 39.
    Tackett AJ, Morris PD, Dennis R et al. Unwinding of unnatural substrates by a DNA helicase. Biochemistry 2001; 40(2):543–548.PubMedCrossRefGoogle Scholar
  40. 40.
    Died G, Corradini R, Sforza S et al. Inhibition of RNA polymerase III elongation by a T10 peptide nucleic acid. J Biol Chem 2001; 276(8):5720–5725.CrossRefGoogle Scholar
  41. 41.
    Bentin T, Nielsen PE. Enhanced peptide nucleic acid binding to supercoiled DNA: Possible implications for DNA breathing dynamics. Biochemistry 1996; 35(27):8863–8869.PubMedCrossRefGoogle Scholar
  42. 42.
    Wahle E, Ruegsegger U. 3′-End processing of premRNA in eukaryotes. FEMS Microbiol Rev 1999; 23(3):277–295.PubMedGoogle Scholar
  43. 43.
    Vickers TA, Wyatt JR, Burckin T et al. Fully modified 2′ MOE oligonucleotides redirect polyadenylation. Nucleic Acids Res 2001; 29(6):1293–1299.PubMedCrossRefGoogle Scholar
  44. 44.
    Horowitz DS, Krainer AR. Mechanisms for selecting 5′ splice sites in mammalian premRNA splicing. Trends Genet 1994; 10(3):100–106.PubMedCrossRefGoogle Scholar
  45. 45.
    Sierakowska H, Sambade MJ, Schumperli D et al. Sensitivity of splice sites to antisense oligonucleotides in vivo. RNA 1999; 5(3):369–377.PubMedCrossRefGoogle Scholar
  46. 46.
    Lacerra G, Sierakowska H, Carestia C et al. Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. Proc Nad Acad Sci USA 2000; 97(17):9591–9596.CrossRefGoogle Scholar
  47. 47.
    Karras JG, Maier MA, Lu T et al. Peptide nucleic acids are potent modulators of endogenous premrna splicing of the murine interleukin-5 receptor-alpha chain. Biochemistry 2001; 40(26):7853–7859.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee R, Kaushik N, Modak MJ et al. Polyamide nucleic acid targeted to the primer binding site of the HIV-1 RNA genome blocks in vitro HIV-1 reverse transcription. Biochemistry 1998; 37(3):900–910.PubMedCrossRefGoogle Scholar
  49. 49.
    Boulme F, Freund F, Moreau S et al. Modified (PNA, 2′-O-methyl and phosphoramidate) anti-TAR antisense oligonucleotides as strong and specific inhibitors of in vitro HIV-1 reverse transcription. Nucleic Acids Res 1998; 26(23):5492–5500.PubMedCrossRefGoogle Scholar
  50. 50.
    Mouscadet JF, Carteau S, Goulaouic H et al. Triplex-mediated inhibition of HIV DNA integration in vitro. J Biol Chem 1994; 269(34):21635–21638.PubMedGoogle Scholar
  51. 51.
    Bouziane M, Cherny DI, Mouscadet JF et al. Alternate strand DNA triple helix-mediated inhibition of HIV-1 U5 long terminal repeat integration in vitro. J Biol Chem 1996; 271(17):10359–10364.PubMedCrossRefGoogle Scholar
  52. 52.
    Mayhood T, Kaushik N, Pandey PK et al. Inhibition of Tat-mediated transactivation of HIV-1 LTR transcription by polyamide nucleic acid targeted to TAR hairpin element. Biochemistry 2000; 39(38):11532–11539.PubMedCrossRefGoogle Scholar
  53. 53.
    Vickers TA, Ecker DJ. Enhancement of ribosomal frameshifting by oligonucleotides targeted to the HIV gag-pol region. Nucleic Acids Res 1992; 20(15):3945–3953.PubMedCrossRefGoogle Scholar
  54. 54.
    Lodmell JS, Ehresmann C, Ehresmann B et al. Structure and dimerization of hiv-1 kissing loop aptamers. J Mol Biol 2001; 311(3):475–490.PubMedCrossRefGoogle Scholar
  55. 55.
    Zennou V, Petit C, Guetard D et al. HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 2000; 101(2):173–185.PubMedCrossRefGoogle Scholar
  56. 56.
    Hiratou T, Tsukahara S, Miyano-Kurosaki N et al. Inhibition of HIV-1 replication by a two-strand system (FTFOs) targeted to the polypurine tract. FEES Lett 1999; 456(1):186–190.CrossRefGoogle Scholar
  57. 57.
    Faria M, Wood CD, Perrouault L et al. Targeted inhibition of transcription elongation in cells mediated by triplex-forming oligonucleotides. Proc Natl Acad Sci USA 2000; 97(8):3862–3867.PubMedCrossRefGoogle Scholar
  58. 58.
    Malchere C, Verheijen J, van der Laan S et al. A short phosphodiester window is sufficient to direct RNase H-dependent RNA cleavage by antisense peptide nucleic acid. Antisense Nucleic Acid Drug Dev 2000; 10(6):463–468.PubMedGoogle Scholar
  59. 59.
    Verheijen JC, Chen L, Bayly SF et al. Synthesis and RNAse L binding and activation of a 2-5A-(5′)-DNA-(3′)-PNA chimera, a novel potential antisense molecule. Nucleosides Nucleotides Nucleic Acids 2000; 19(10–12):1821–1830.PubMedGoogle Scholar
  60. 60.
    Verheijen JC, van der Marel GA, van Boom JH et al. 2,5-oligoadenylate-peptide nucleic acids (2-5A-PNAs) activate RNase L. Bioorg Med Chem 1999; 7(3):449–455.PubMedCrossRefGoogle Scholar
  61. 61.
    Verheijen JC, Bayly SF, Player MR et al. 2-5A-PNA complexes: A novel class of antisense compounds. Nucleosides Nucleotides 1999; 18(6–7):1485–1486.PubMedGoogle Scholar
  62. 62.
    Wang Z, Chen L, Bayly SF et al. Convergent synthesis of ribonuclease L-active 2′,5′-oligoadenylate-peptide nucleic acids. Bioorg Med Chem Lett 2000; 10(12):1357–1360.PubMedCrossRefGoogle Scholar
  63. 63.
    Bigey P, Sonnichsen SH, Meunier B et al. DNA binding and cleavage by a cationic manganese porphyrin-peptide nucleic acid conjugate. Bioconjug Chem 1997; 8(3):267–270.PubMedCrossRefGoogle Scholar
  64. 64.
    Footer M, Egholm M, Kron S et al. Biochemical evidence that a D-loop is part of a four-stranded PNA-DNA bundle. Nickel-mediated cleavage of duplex DNA by a Gly-Gly-His bis-PNA. Biochemistry 1996; 35(33):10673–10679.PubMedCrossRefGoogle Scholar
  65. 65.
    Armitage B, Koch T, Frydenlund H et al. Peptide nucleic acid-anthraquinone conjugates: Strand invasion and photoinduced cleavage of duplex DNA. Nucleic Acids Res 1997; 25(22):4674–4678.PubMedCrossRefGoogle Scholar

Copyright information

© and Kluwer Academic / Plenum Publishers 2006

Authors and Affiliations

  • Lionel Bastide
    • 1
  • Bernard Lebleu
    • 1
  • Ian Robbins
    • 2
  1. 1.Institute de Génétique Moléculaire de Montpellier Centre National de la Recherche ScientifiqueUniversite Montpellier 2 UMR 5124, IGMMMontpellierFrance
  2. 2.Institute de Génétique Moléculaire de MontpellierCentre National de la Recherche ScientifiqueMontpellierFrance

Personalised recommendations