Skip to main content
SpringerLink
Log in

Antigene, Ribozyme and Aptamer Nucleic Acid Drugs: Progress and Prospects

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Nucleic acids are increasingly being considered for therapeutic uses, either to interfere with the function of specific nucleic acids or to bind specific proteins. Three types of nucleic acid drugs are discussed in this review: aptamers, compounds which bind specific proteins; triplex forming (antigene) compounds; which bind double stranded DNA; and ribozymes (catalytic RNA), which bind and cleave RNA targets. The binding of aptamers to protein may involve specific sequence recognition, although this is not always the case. The interaction of triplex forming oligonucleotides or ribozymes with their targets always involves specific sequence recognition and hybridization. Early optimism concerning the possibility of designing drugs without a priori knowledge of the structure of the target (except a nucleotide sequence) has been tempered by the finding that target structure has a dramatic effect upon the hybridization potential of the nucleic acid drug. Other obstacles to the creation of effective nucleic acid drugs are their relative high molecular weight (>3300) and their sensitivity to degradation. The molecular weight of these compounds has created a significant delivery problem which needs to be solved if nucleic acid drugs are to become effective therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. G. Zon. Oligonucleotide analogues as potential chemotherapeutic agents. Pharmaceut. Res. 5:539–549 (1988).

    Google Scholar 

  2. J. Y. Tang, J. Temsamani, and S. Agrawal. Self-stabilized antisense oligonucleotide phosphorothioates: properties and anti-HIV activity. Nucleic Acids Res. 21:2729–2735 (1993).

    Google Scholar 

  3. E. Uhlmann and A. Peyman. Antisense oligonucleotides: A new therapeutic principle. Chemical Reviews 90:544–584 (1990).

    Google Scholar 

  4. C. Hélène and J. J. Toulmé. Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim. Biophys. Acta 1049:99–125 (1990).

    Google Scholar 

  5. C. K. Mirabelli, C. F. Bennett, K. Anderson, and S. T. Crooke. In vitro and in vivo pharmacologic activities of antisense oligonucleotides. Anti-Cancer Drug Design 6:647–661 (1991).

    Google Scholar 

  6. P. D. Cook. Medicinal chemistry strategies for antisense research. In S. T. Crooke and B. Lebleu (eds.) Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 149–187.

    Google Scholar 

  7. A. D. Ellington and J. W. Szostak. In vitro selection of RNA molecules that bind specific ligands. Nature (London). 346:818–822 (1990).

    Google Scholar 

  8. A. Bielinska, R. A. Shivdasani, L. Zhang, and G. J. Nabel. Regulation of gene expression with double-stranded phosphorothioate oligonucleotides. Science 250:997–1000 (1990).

    Google Scholar 

  9. K. C. Ess, J. J. Hutton, and B. J. Aronow. Double-stranded phosphorothioate oligonucleotide modulation of gene expression. Annals New York Acad. Sci. 716:321–332 (1994).

    Google Scholar 

  10. L. C. Bock, L. C. Griffin, J. A. Latham, E. H. Vermaas, and J. J. Toole. Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature (London) 255:564–566 (1992).

    Google Scholar 

  11. L. C. Griffin, G. F. Tidmarsh, L. C. Bock, J. J. Toole, and L. L. K. Leung. In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal circuits. Blood 12:3271–3276 (1993).

    Google Scholar 

  12. K. Y. Wang, S. McCurdy, R. G. Shea, S. Swaminathan, and P. H. Bolton. A DNA aptamer which binds to and inhibits thrombin exhibits a new structural motif for DNA. Biochemistry 32:1899–1904 (1993).

    Google Scholar 

  13. K. Padmanabhan, K. P. Padmanbhan, J. D. Ferrara, J. E. Sadler, and A. Tulinsky. The structure of α-thrombin inhibited by a 15-mer single-stranded DNA aptamer. J. Biol. Chem. 268:17561–17654 (1993).

    Google Scholar 

  14. L. R. Paborsky, S. N. McCurdy, L. C. Griffin, J. J. Toole, and L. L. K. Keung. The single-stranded DNA aptamer-binding site of human thrombin. J. Biol. Chem. 268:20808–20811 (1993).

    Google Scholar 

  15. B. A. Sullenger, H. F. Gallardo, G. E. Ungers, and E. Gilboa. (1990). Overexpression of TAR sequences renders cells resistant to human immunodeficiency virus replication. Cell 63:601–608 (1990).

    Google Scholar 

  16. J. Lisziewicz, D. Sun, J. Smythe, P. Lusso, F. Lori, A. Louie, P. Markham, J. J. Rossi, M. Reitz, and R. C. Gallo. Inhibition of human immunodeficiency virus type 1 replication by regulated expression of a polymeric Tat activation response RNA decoy as a strategy for gene therapy in AIDS. Proc. Natl. Acad. Sci. USA. 90:8000–8004 (1993).

    Google Scholar 

  17. F. Birg, D. Praseuth, A. Zerial, N. T. Thuong, U. Asseline, T. LeDoan, and C. Hélène. Inhibition of Simian virus 40 DNA replication in CV-1 cells by an oligodeoxynucleotide covalently linked to an intercalating agent. Nucleic Acids Res. 18:2901–2908 (1990).

    Google Scholar 

  18. H. E. Moser and P. B. Dervan. Sequence-specific cleavage of double helical DNA by triple helix formation. Science 238:645–650 (1987).

    Google Scholar 

  19. P. A. Beal and P. B. Dervan. Second structural motif for recognition of DNA by oligonucleotide-directed triple-helix formation. Science 251:1360–1363 (1991).

    Google Scholar 

  20. M. Cooney, C. Czernuszewicz, E. H. Postel, S. J. Flint, and M. E. Hogan. Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro. Science 241:456–459 (1988).

    Google Scholar 

  21. R. H. Durland, D. J. Kessler, S. Gunnell, M. Duvic, B. M. Pettitt, and M. E. Hogan. Binding of triple helix forming oligonucleotides to sites in gene promoters. Biochemistry 30:9246–9255 (1991).

    Google Scholar 

  22. F. M. Orson, D. W. Thomas, W. M. McShan, D. J. Kesler, and M. E. Hogan. Oligonucleotide inhibition of IL2Rα mRNA transcription by promoter region collinear triplex formation in lymphocytes. Nucleic Acids Res. 19:3435–3441 (1991).

    Google Scholar 

  23. W. M. McShan, R. D. Rossen, A. H. Laughter, J. Trial, D. J. Kessler, J. G. Zendegui, M. E. Hogan, and F. M. Orson. Inhibition of transcription of HIV-1 in infected human cells by oligodeoxynucleotides designed to form DNA triple helices. J. Biol. Chem. 267:5712–5721 (1992).

    Google Scholar 

  24. J. S. Sun, T. DeBizemont, T. Duval-Valentin, T. Montenay-Garestier, and C. Hélène. Extension of the range of recognition sequences for triple helix formation by oligonucleotides containing guanines and thymines. Comptes Rend. Acad. Sci. Paris, Série III 313:585–590 (1991).

    Google Scholar 

  25. J. S. Sun, C. Giovannangeli, J. C. François, R. Kurfurst, T. Montenay-Garestier, U. Asseline, T. Saison-Behmoaras, N. T. Thuong, and C. Hélène. Triple-helix formation by α oligodeoxynucleotides and α-oligodeoxynucleotide-intercalator conjugates. Proc. Natl. Acad. Sci USA 88:6023–6027 (1991).

    Google Scholar 

  26. S. D. Jayasena and B. H. Johnston. Oligonucleotide-directed triple helix formation at adjacent oligopurine and oligopyrimidine DNA tracts by alternate strand recognition. Nucleic Acids Res. 20:5279–5288 (1992).

    Google Scholar 

  27. S. D. Jayasena and B. H. Johnston. Sequence limitations to triple helix formation by alternate-strand recognition. Biochemistry 32:2800–2807 (1993).

    Google Scholar 

  28. S. Volkmann, J. Dannull, and K. Moeling. The polypurine tract, PPT, of HIV as target for antisense and triple-helix-forming oligonucleotides. Biochemie 75:71–78 (1993).

    Google Scholar 

  29. E. Brossalina, E. Pascolo, and J. J. Toulmé. The binding of an antisense oligonucleotide to a hairpin structure via triplex formation inhibits chemical and biological reactions. Nucleic Acids Res. 21:5616–5622 (1993).

    Google Scholar 

  30. C. Giovannangeli, N. T. Thuong, and C. Hélène. Oligonucleotide clamps arrest DNA synthesis on a single-stranded DNA target. Proc. Natl. Acad. Sci. USA 90:10013–10017 (1993).

    Google Scholar 

  31. T. J. Povsic and P. B. Dervan. Triple helix formation by oligonucleotides on DNA extended to the physiological pH range. J. Am. Chem. Soc. 111:3059–3061 (1989).

    Google Scholar 

  32. A. Ono, P. O. P. Ts'o, and L-S. Kan. Triplex formation of oligonucleotides containing 2′-O-methylpseudocytidine in substitution for 2′-deoxycytidine. J. Amer. Chem. Soc. 113:4032–4033 (1991).

    Google Scholar 

  33. S. H. Krawczyk, J. F. Milligan, S. Wadwani, C. Moulds, B. C. Froehler, and M. D. Matteucci. Oligonucleotide-mediated triple helix formation using an N3-protonated deoxycytidine analog exhibiting pH-independent binding within the physiological range. Proc. Natl. Acad. Sci. USA. 89:3761–3764 (1992).

    Google Scholar 

  34. J. S. Koh and P. B. Dervan. Design of nonnatural deoxyribonucleoside for recognition of GC base pairs by oligonucleotidedirected triple helix formation. J. Amer. Chem. Soc. 114:1470–1478 (1992).

    Google Scholar 

  35. M. C. Jetter and F. W. Hobbs. 7,8-Dihydro-8-oxoadenine as a replacement for cytosine in the third strand of triple helices. Triplex formation without hypochromicity. Biochemistry 32:3249–3254 (1993).

    Google Scholar 

  36. N. Colocci and P. B. Dervan. Cooperative binding of 8-mer oligonucleotides containing 5-(1-propynyl)-2′-deoxyuridine to adjacent DNA sites by triple-helix formation. J. Amer. Chem. Soc. 116:786–786 (1993).

    Google Scholar 

  37. L. J. Maher III, P. B. Dervan, and B. Wold. Kinetic analysis of oligonucleotide-directed triple-helix formation on DNA. Biochemistry 29:8820–8826 (1990).

    Google Scholar 

  38. M. Rougée, B. Faucon, J-L. Mergny, F. Barcelo, C. Giovannangeli, T. Garestier, and C. Hélène. Kinetics and thermodynamics of triple-helix formation: Effects of ionic strength and mismatches. Biochemistry 31:9269–9278 (1992).

    Google Scholar 

  39. J-L. Mergny, J-S. Sun, M. Rougée, T. Montenay-Garestier, F. Barcelo, J. Chomilier, and C. Hélène. Sequence specificity in triple-helix formation: Experimental and theoretical studies of the effect of mismatches on triplex stability. Biochemistry 30:9791–9798 (1991).

    Google Scholar 

  40. J-S. Sun, J. C. François, T. Montenay-Garestier, T. Saison-Behmoaras, V. Roig, N. T. Thuong, and C. Hélène. Sequencespecific intercalating agents: Intercalation at specific sequences on duplex DNA via major groove recognition by oligonucleotide-intercalator conjugates. Proc. Natl. Acad. Sci. USA 86:9194–9202 (1989).

    Google Scholar 

  41. S. M. Gryaznov and D. H. Lloyd. Modulation of oligonucleotide duplex and triplex stability via hydrophobic interactions. Nucleic Acids Res. 21:5909–5915 (1993).

    Google Scholar 

  42. J.-F. Mouscadet, C. Ketterlé, H. Goulaouic, S. Carteau, F. Subra, M. LeBret, and C. Auclair. Triple helix formation with short oligonucleotide-intercalator conjugates matching the HIV-1 U3 LTR end sequence. Biochemistry 33:4187–4196 (1994).

    Google Scholar 

  43. J-L. Mergny, G. Duval-Valentin, C. H. Nguyen, L. Perrouault, B. Faucon, M. Rougée, T. Montenay-Garestier, E. Bisagni, and C. Hélène. Triple Helix-Specific Ligands. Science 256:1681–1684 (1992).

    Google Scholar 

  44. D. S. Pilch, M. J. Waring, J-S. Sun, M. R. Rougée, C-H. Nguyen, E. Bisagni, T. Garestier, and C. Hélène. Characterization of a triple helix-specific ligand. J. Mol. Biol. 232:926–948 (1993).

    Google Scholar 

  45. W. D. Wilson, F. A. Tanious, S. Mizan, S. Yao, A. S. Kiselyov, G. Zon, and L. Strekowski. DNA triple-helix specific intercalators as antigene enhancers: unfused aromatic cations. Biochemistry 32:10614–10621 (1993).

    Google Scholar 

  46. F. M. Orson, B. M. Kinsel, and W. M. McShan. Linkage structures strongly influence the binding cooperativity of DNA intercalators conjugated to triplex forming oligonucleotides. Nucleic Acids Res. 22:479–484 (1994).

    Google Scholar 

  47. S. L. Young, S. H. Krawczyk, M. D. Matteucci, and J. J. Toole (1991). Triple helix formation inhibits transcription elongation in vitro. Proc. Natl. Acad. Sci USA 88:10023–10026 (1991).

    Google Scholar 

  48. M. Takasugi, A. Guendouz, M. Chassignol, J. L. Decout, J. L'homme, N. T. Thuong, and C. Hélène, C. (1991). Sequencespecific photo-induced cross-linking of the two strands of double-helical DNA by a psoralen covalently linked to a triple helix-forming oligonucleotide. Proc. Natl. Acad. Sci. USA 88:5602–5606 (1991).

    Google Scholar 

  49. M. Grigoriev, D. Praseuth, A. L. Guieysse, P. Robin, N. T. Thuong, C. Hélène, and A. Harel-Bellan. Inhibition of gene expression by triple helix-directed DNA cross-linking at specific sites. Proc. Natl. Acad. Sci. USA 90:3501–3505 (1993).

    Google Scholar 

  50. J. C. François, T. Saison-Behmoaras, C. Barbier, M. Chassignol, N. T. Thuong, and C. Hélène. Sequence-specific recognition and cleavage of duplex DNA via triple-helix formation by oligonucleotides covalently linked to a phenanthrolinecopper chelate. Proc. Natl. Acad. Sci. USA. 86:9702–9706 (1989).

    Google Scholar 

  51. M. Shimizu, I. Inoue, and E. Ohtsuka. Detailed study of sequence-specific DNA cleavage of triplex forming oligonucleotides linked to 1,10-phenanthroline. Biochemistry 33:606–613 (1994).

    Google Scholar 

  52. L. Perrouault, U. Asseline, C. Rivalle, N. T. Thuong, E. Bisagni, C. Giovannangeli, T. LeDoan, and C. Hélène. Sequencespecific artificial photo-induced endonucleases based on triplehelix forming oligonucleotides. Nature (London) 344:358–360 (1990).

    Google Scholar 

  53. J. U. Skoog and L. J. Maher. Repression of bacteriophage promoters by DNA and RNA oligonucleotides. Nucleic Acids Res. 21:2131–2138 (1993).

    Google Scholar 

  54. L. J. Maher III. Inhibition of T7 RNA polymerase initiation by triple-helical DNA complexes: A model for artificial gene repression. Biochemistry 31:7585–7594 (1992).

    Google Scholar 

  55. J. C. François, T. Saison-Behmoaras, N. T. Thuong, and C. Hélène. Inhibition of restriction endonuclease cleavage via triple helix formation by homopyrimidine oligonucleotides. Biochemistry 28:9617–9619 (1989).

    Google Scholar 

  56. L. J. Maher III, B. Wold, and P. B. Dervan. Inhibition of DNA binding proteins by oligonucleotide-directed triple helix formation. Science 245:725–730 (1989).

    Google Scholar 

  57. J. C. Hanvey, M. Shimizu, and R. D. Wells. Site-specific inhibition of EcoRI restriction/modification enzymes by a DNA triple helix. Nucleic Acids Res. 18:157–161 (1990).

    Google Scholar 

  58. J. E. Gee, S. Blume, R. C. Snyder, R. Rat, and D. M. Miller. Triplex formation prevents Sp 1 binding to the Dihydrofolate Reductase promoter. J. Biol. Chem. 267:11163–11167 (1992).

    Google Scholar 

  59. C. Ross, M. Samuel, and S. L. Broitman. Transcriptional inhibition of the bacteriophage T7 early promoter region by oligonucleotide triple helix formation. Biochem. Biophys. Res. Commun. 189:1674–1680 (1992).

    Google Scholar 

  60. J. U. Skoog and L. J. Maher III. Relief of triple-helix-mediated promoter inhibition by elongating RNA polymerases. Nucleic Acids Res. 21:4055–4058 (1993).

    Google Scholar 

  61. R. F. Rando, L. DePaolis, R. H. Durland, K. Jayaraman, D. J. Kessler, and M. E. Hogan. Inhibition of T7 and T3 RNA polymerase directed transcription elongation in vitro. Nucleic Acids Res. 22:678–685 (1994).

    Google Scholar 

  62. P. S. Sarkar and S. K. Brahmachari. Intramolecular triplex potential sequence within a gene down regulates its expression in vivo. Nucleic Acids Res. 20:5713–5718 (1992).

    Google Scholar 

  63. J. G. Hacia, P. B. Dervan, and B. J. Wold. Inhibition of Klenow fragment DNA polymerase on double-helical templates by oligonucleotide-directed triple-helix formation. Biochemistry 33:6192–6200 (1994).

    Google Scholar 

  64. G. Duval-Valentin, N. T. Thuong, and C. Hélène. Specific inhibition of transcription by triple-helix forming oligonucleotides. Proc. Natl. Acad. Sci. USA 89:504–508 (1992).

    Google Scholar 

  65. G. Degols, J-P. Clarenc, B. Lebleu, and J-P. Léonetti. Reversible inhibition of gene expression by a psoralen functionalized triple helix forming oligonucleotide in intact cells. J. Biol. Chem. 269:16933–16937 (1994).

    Google Scholar 

  66. J. C. Hanvey, N. J. Peffer, J. E. Bisi, S. A. Thomson, R. Cadilla, J. A. Josey, D. J. Ricca, F. Hassman, M. A. Bonham, K. G. Au, S. G. Carter, D. A. Bruckenstein, A. L. Boyd, S. A. Noble, and L. E. Babiss. Antisense and antigene properties of peptide nucleic acids. Science 258:1481–1485 (1992).

    Google Scholar 

  67. P. E. Nielsen, M. Egholm, R. H. Berg, and O. Buchardt. Sequence selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254:1497–1500 (1991).

    Google Scholar 

  68. M. Grigoriev, D. Praseuth, P. Robin, A. Hemar, T. Saison-Behmoaras, A. Dautry-Varsat, N. T. Thuong, C. Hélène, and A. Harel-Bellan. A triple helix-forming oligonucleotide-intercalator conjugate acts as a transcriptional repressor via inhibition of NF κB binding to interleukin-2 receptor α-regulatory sequence. J. Biol. Chem. 267:3389–3395 (1992).

    Google Scholar 

  69. C. Roy. Inhibition of gene transcription by purine rich triplex forming oligodeoxyribonucleotides. Nucleic Acids Res. 21:2845–2852 (1993).

    Google Scholar 

  70. N. H. Ing, J. M. Beekman, D. J. Kessler, M. Murphy, K. Jayaraman, J. G. Zendegui, M. E. Hogan, B. W. O-Malley, and M-J. Tsai. In vivo transcription of a progesterone-responsive gene is specifically inhibited by a triple-forming oligonucleotide. Nucleic Acids Res. 21:2789–2796 (1993).

    Google Scholar 

  71. E. H. Postel, S. J. Flint, D. J. Kessler, and M. E. Hogan. Evidence that a triplex-forming oligodeoxyribonucleotide binds to the c-myc promoter in HeLa cells, thereby reducing c-myc mRNA levels. Proc. Natl. Acad. Sci. USA 88:8227–8231 (1991).

    Google Scholar 

  72. C. W. Helm, K. Shrestha, S. Thomas, H. Shingleton, and D. Miller. A unique c-myc targeted triplex forming oligonucleotide inhibits the growth of ovarian and cervical carcinomas in vitro. Gynecologic. Oncol. 49:339–343 (1993).

    Google Scholar 

  73. S. G. Kim, S. Tsukahara, S. Yokoyama, and H. Takaku. The influence of oligodeoxyribonucleotide phosphorothioate pyrimidine strands on triplex formation. FEBS Lett. 314:29–32 (1992).

    Google Scholar 

  74. S. Tsukahara, S-G. Kim, and H. Takaku. Inhibition of restriction endonuclease cleavage site via triple helix formation by homopyrimidine phosphorothioate oligonucleotides. Biochem. Biophys. Res. Commun. 196:990–996 (1993).

    Google Scholar 

  75. J. P. Clarenc, G. Degols, J. P. Léonetti, P. Milhaud, and B. Lebleu. Delivery of antisense oligonucleotides by poly(L-lysine) conjugation and liposome encapsulation. Anti-Cancer Drug Design 8:81–94 (1993).

    Google Scholar 

  76. R. L. Juliano and S. Akhtar. Liposomes as a drug delivery system for antisense oligonucleotides. Antisense Res. Dev. 2:165–176 (1992).

    Google Scholar 

  77. C. F. Bennett, M-Y. Chiang, H. Chan, J. E. Shomaker, and C. K. Mirabelli. Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Molecular Pharmacol. 41:1023–1033 (1992).

    Google Scholar 

  78. T. R. Cech. Ribozyme engineering. Current Opinion in Structural Biology 2:605–609 (1992).

    Google Scholar 

  79. R. H. Symons. Small catalytic RNAs. Annu. Rev. Biochem. 61:641–671 (1992).

    Google Scholar 

  80. H. D. Robertson, S. Altman, and D. J. Smith. Purification and properties of a specific Escherichia coli ribonuclease which cleaves a tyrosine transfer ribonucleic acid precursor. J. Biol. Chem. 247:5243–5251 (1972).

    Google Scholar 

  81. W. H. McClain, C. Guerrier-Takada, and S. Altman. Model substrates for an RNA enzyme. Science 238:527–530 (1987).

    Google Scholar 

  82. K. Kruger, P. J. Grabowski, A. J. Zaug, J. Sands, D. E. Gottschling, and T. R. Cech. Self-splicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell 31:147–157 (1982).

    Google Scholar 

  83. A. J. Zaug, M. D. Been, and T. R. Cech. The Tetrahymena ribozyme acts like an RNA restriction endonuclease. Nature 324:429–433 (1986).

    Google Scholar 

  84. A. C. Forster and R. H. Symons. Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active site. Cell 49:211–220 (1987).

    Google Scholar 

  85. A. C. Forster and R. H. Symons. Self-cleavage of virusoid RNA is performed by the proposed 55-nucleotide active site. Cell 50:9–16 (1987).

    Google Scholar 

  86. O. C. Uhlenbeck A small catalytic oligonucleotide. Nature 328:596–600 (1987).

    Google Scholar 

  87. M. Koizumi, S. Iwai, and E. Ohtsuka. Construction of a series of several self-cleaving RNA duplexes using synthetic 21-mers. FEBS Lett 228:228–230 (1988).

    Google Scholar 

  88. M. Koizumi, S. Iwai, and E. Ohtsuka. Cleavage of specific sites of RNA by designed ribozymes. FEBS Lett 239:285–288 (1988).

    Google Scholar 

  89. J. Haseloff and W. L. Gerlach. Simple RNA enzymes with new and highly specific endoribonuclease activities. Nature (London) 334:585–591 (1988).

    Google Scholar 

  90. F. H. Cameron and P. A. Jennings. Specific gene suppression by engineered ribozymes in monkey cells. Proc. Natl. Acad. Sci. USA 86:9139–9143 (1989).

    Google Scholar 

  91. A. Hampel and R. Tritz. RNA catalytic properties of the minimum (−)sTRSV sequence. Biochemistry 28:4929–4933 (1989)

    Google Scholar 

  92. P. A. Feldstein, J. M. Buzayan, and G. Bruening. Two sequences participating in the autocatalytic processing of satellite tobacco ringspot virus complementary RNA. Gene 82:53–61 (1989).

    Google Scholar 

  93. J. Haseloff and W. L. Gerlach. Sequences required for self-catalyzed cleavage of the satellite RNA of tobacco ringspot virus. Gene 82:43–52 (1989).

    Google Scholar 

  94. A. Hampel, R. Tritz, M. Hicks and P. Cruz. Hairpin catalytic RNA model: Evidence for helices and sequence requirement for substrate RNA. Nucleic Acids Res. 18:299–304 (1990).

    Google Scholar 

  95. P. A. Feldstein, J. M. Buzayan, H. van Tol, J. DeBear, G. R. Gough, P. T. Gilham, and G. Bruening. Specific association between an endoribonucleolytic sequence from a satellite RNA and a substrate analogue containing a 2′–5′ phosphodiester. Proc. Natl. Acad. Sci. USA. 87:2623–2627 (1990).

    Google Scholar 

  96. D. E. Ruffner, G. D. Stormo, and O. C. Uhlenbeck. Sequence requirements of the hammerhead RNA self-cleavage reaction. Biochemistry 29:10695–10702 (1990).

    Google Scholar 

  97. A. Berzal-Herranz, S. Joseph, B. M. Chowrira, S. E. Butcher, and J. M. Burke. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. 12:2567–2574 (1993).

    Google Scholar 

  98. P. Anderson, J. Monforte, R. Tritz, S. Nesbitt, J. Hearst, and A. Hampel. Mutagenesis of the hairpin ribozyme. Nucleic Acids Res. 22:1096–1100 (1994).

    Google Scholar 

  99. B. M. Chowrira, A. Berzal-Herranz, and J. M. Burke. Novel guanosine requirement for catalysis by the hairpin ribozyme. Nature (London) 354:320–322 (1991).

    Google Scholar 

  100. J. O. Ojwang, A. Hampel, D. J. Looney, F. Wong-Staal, and J. Rappaport. Inhibition of human immunodeficiency virus type-1 expression by a hairpin ribozyme. Proc. Natl. Acad. Sci. USA. 89:10802–10806 (1992).

    Google Scholar 

  101. S. Joseph, A. Berzal-Herranz, B. M. Chowrira, S. E. Butcher, and J. M. Burke. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes and Development 7:130–138 (1993).

    Google Scholar 

  102. C. Guerrier-Takada, K. Gardiner, T. Marsh, N. Pace, and S. Altman. The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell 35:849–857 (1983).

    Google Scholar 

  103. A. C. Forster and S. Altman. External guide sequences for an RNA enzyme. Science 249:783–786 (1990).

    Google Scholar 

  104. Y. Yuan, E-S. Hwang, and S. Altman. Targeted cleavage of mRNA by human RNase P. Proc. Natl. Acad. Sci. USA 89:8006–8010 (1992).

    Google Scholar 

  105. A. T. Perrotta and M. D. Been. Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis δ virus RNA sequence. Biochemistry 31:16–21 (1992).

    Google Scholar 

  106. M. D. Been, A. T. Perrotta, and S. P. Rosenstein. Secondary structure of the self-cleaving RNA of hepatitis delta virus: Applications to catalytic RNA design. Biochemistry 31:11843–11852 (1992).

    Google Scholar 

  107. Y. Prasad, J. B. Smith, P. A. Gottlieb, J. Bentz, and G. Dinter-Gottlieb. Deriving a 67-nucleotide trans-cleaving ribozyme form the hepatitis delta virus antigenomic RNA. Antisense Res. Dev. 2:267–277 (1992).

    Google Scholar 

  108. M. Puttaraju, A. T. Perrotta, and M. D. Been. A circular transacting hepatitis delta virus ribozyme. Nucleic Acids Res. 21:4253–4258 (1993).

    Google Scholar 

  109. F. Lescure, M. Blumenfeld, G. Thill, M. Vasseur, and N. K. Tanner. Trans cleavage of RNA substrates by an HDV-derived ribozyme. Progress in Clinical and Biological Res. 382:99–108 (1993).

    Google Scholar 

  110. K. J. Hertel, D. Herschlag, and O. C. Uhlenbeck. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction. Biochemistry 33:3374–3385 (1994).

    Google Scholar 

  111. J. M. Buzayan, W. L. Gerlach, and G. Bruening. Spontaneous ligation of RNA fragments with sequences that are complementary to a plant virus satellite RNA. Nature (London) 323:349–353 (1986).

    Google Scholar 

  112. G. A. Prody, J. T. Bakos, J. M. Buzayan, I. R. Shneider, and G. Bruening. Autolytic processing of dimeric plant virus satellite RNA. Science 231:1577–1580 (1986)

    Google Scholar 

  113. H. von Tol, J. M. Buzayan, and G. Bruening. Evidence for spontaneous circle formation in the replication of satellite RNA of tobacco ringspot virus. Virology 180:23–30 (1991).

    Google Scholar 

  114. E. Bertrand, R. Pictet, and T. Grange. Can hammerhead ribozymes be efficient tools to inactivate gene function? Nucleic Acids Res. 22:293–300 (1993).

    Google Scholar 

  115. A. J. Zaug, C. A. Grosshans, and T. R. Cech. Sequence-specific endoribonuclease activity of the Tetrahymena ribozyme: Enhanced cleavage of certain oligonucleotide substrates that form mismatched ribozyme-substrate complexes. Biochemistry 27:8294–8931 (1988).

    Google Scholar 

  116. J. A. McSwiggen and T. R. Cech. Stereochemistry of RNA cleavage by the Tetrahymena ribozyme and evidence that the chemical step is not rate-limiting. Science 244:679–683 (1989).

    Google Scholar 

  117. J. Goodchild and V. Kohli. Ribozymes that cleave an RNA sequence from human immunodeficiency virus: The effect of flanking sequence on rate. Arch. Biochem Biophys. 284:286–391 (1991).

    Google Scholar 

  118. D. Herschlag. Implications of ribozyme kinetics for targeting the cleavage of specific RNA molecules in vivo: More isn't always better. Proc. Natl. Acad. Sci. USA 88:6921–6925 (1991).

    Google Scholar 

  119. H. Kobayashi, N. Kim, M-E. Halatsch, and T. Ohnuma. Specificity of ribozyme designed for mutated DHFR mRNA. Biochemical Pharmacology 47:1607–1613 (1994).

    Google Scholar 

  120. J. Ellis and J. Rogers. Design and specificity of hammerhead ribozymes against calretinin mRNA. Nucleic Acids Res. 21:5171–5178 (1993).

    Google Scholar 

  121. Z. Tsuchihashi, M. Khosla, and D. Herschlag. Protein enhancement of hammerhead ribozyme catalysis. Science 262:99–102 (1993).

    Google Scholar 

  122. E. L. Bertrand and J. J. Rossi. Facilitation of hammerhead ribozyme catalysis by the nucleocapsid protein of HIV-1 and the heterogeneous nuclear ribonucleoprotein A1. EMBO J. 13:2904–2912 (1994).

    Google Scholar 

  123. J. Goodchild. Enhancement of ribozyme catalytic activity by a contiguous oligodeoxynucleotide (facilitator) and by 2′-O-methylation. Nucleic Acids Res. 20:4607–4612 (1991).

    Google Scholar 

  124. S. K. Saxena and E. J. Ackerman. Ribozymes correctly cleave a model substrate and endogenous RNA in vivo. J. Biol. Chem. 265:17106–17109 (1990).

    Google Scholar 

  125. P. Steinecke, T. Herget, and P. H. Schreier. Expression of a chimeric ribozyme gene results in endonucleolytic cleavage of target mRNA and a concomitant reduction of gene expression in vivo. EMBO J. 11:1525–1530 (1992).

    Google Scholar 

  126. M. Cotten and M. L. Birnsteil. Ribozyme mediated destruction of RNA in vivo. EMBO J. 8:3861–3866 (1989).

    Google Scholar 

  127. N. Sarver, E. M. Cantin, P. S. Chang, J. A. Zaia, P. A. Ladne, D. A. Stephens, and J. J. Rossi. Ribozymes as potential anti-HIV-1 therapeutic agents. Science 247:1222–1225 (1990).

    Google Scholar 

  128. B. Dropulic, N. A. Lin, M. A. Martin, and K-T. Jeang. Functional characterization of a U5 ribozyme: Intracellular suppression of Human Immunodeficiency Virus Type 1 expression. J. Virol. 66:1432–1441 (1992).

    Google Scholar 

  129. G. H. Cantor, T. F. McElwain, T. A. Birkebak, and G. H. Palmer. Ribozyme cleaves rex/tax mRNA and inhibits bovine leukemia virus expression. Proc. Natl. Acad. Sci. USA 90:10932–10936 (1993).

    Google Scholar 

  130. K. J. Scanlon, L. Jiao, T. Funato, W. Wang, T. Tone, J. J. Rossi, and M. Kashani-Sabet. Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metalothionein. Proc. Natl. Acad. Sci. USA. 88:10591–10595 (1991).

    Google Scholar 

  131. T. Funato, E. Yoshida, L. Jiao, T. Tone, M. Kashani-Sabet, and K. J. Scanlon. The utility of an anti fos ribozyme in reversing cisplatin resistance in human carcinomas. Advan. Enzyme Regul. 32:195–209 (1992).

    Google Scholar 

  132. P. J. L'Huillier, S. R. Davis, and A. R. Bellamy. Cytoplasmic delivery of ribozymes leads to efficient reduction in α-lactalbumin mRNA levels in C127I mouse cells. EMBO J. 11:4411–4418 (1992).

    Google Scholar 

  133. M. Homann, S. Tzortzakaki, K. Rittner, G. Sczakiel, and M. Tabler. Incorporation of the catalytic domain of a hammerhead ribozyme into antisense RNA enhances its inhibitory effect on the replication of human immunodeficiency virus type 1. Nucleic Acids Res. 21:2809–2814 (1993).

    Google Scholar 

  134. J. J. Zhao and L. Pick. Generating loss-of-function phenotypes of the fushi tarazu gene with a targeted ribozyme in Drosophila. Nature (London) 365:448–451 (1993).

    Google Scholar 

  135. M. Cotten, G. Schaffner, and M. L. Birnsteil. Ribozyme, antisense RNA, and antisense DNA inhibition of U7 small nuclear ribonucleoprotein-mediated histone pre-mRNA processing in vitro. Mol. Cell. Biol. 9:4479–4487 (1989)

    Google Scholar 

  136. R. Leventis and J. R. Silvius. Interactions of mammalian cells with lipid dispersions containing novel metabolizable cationic amphiphiles. Biochim. Biophys. Acta 1023:124–132 (1990).

    Google Scholar 

  137. P. Crissell, S. Thompson, and W. James. Inhibition of HIV-1 replication by ribozymes that show poor activity in vitro. Nucleic Acids Res. 21:5251–5255 (1993).

    Google Scholar 

  138. M. Koizumi, H. Kamiya, and E. Ohtsuka. Ribozymes designed to inhibit transformation of NIH3T3 cells by the activated c-Ha-ras gene. Gene 117:179–184 (1992).

    Google Scholar 

  139. M. Koizumi, H. Kamiya, and E. Ohtsuka. Inhibition of the c-Ha-ras gene expression by hammerhead ribozymes containing a stable C(UUCG)G hairpin loop. Biol. Pharm. Bull. 16:879–883 (1993).

    Google Scholar 

  140. M. Kashani-Sabet, T. Funato, V. A. Florenes, O. Fodstad, and K. J. Scanlon. Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme. Cancer Res. 54:900–902 (1994).

    Google Scholar 

  141. Z. Xing and J. L. Whitton. An anti-lymphocytic choriomeningitis virus ribozyme expressed in tissue culture cells diminishes viral RNA levels and leads to a reduction in infectious virus yield. J. Virol. 67:1840–1847 (1993).

    Google Scholar 

  142. M. Weerasinghe, S. E. Liem, S. Asad, S. E. Read, and S. Joshi. Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4 + lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. J. Virol. 65:5531–5534 (1991).

    Google Scholar 

  143. K. M. S. Lo, M. A. Biasolo, G. Dehni, G. Palú, and W. A. Haseltine. Inhibition of replication of HIV-1 by retroviral vectors expressing tat-antisense and anti-tat ribozyme RNA. Virology 190:176–183 (1992).

    Google Scholar 

  144. C-J. Chen, A. C. Banerjea, G. G. Harmison, K. Haglund, and M. Schubert. Multitarget-ribozyme directed to cleave at up to nine highly conserved HIV-1 env RNA regions inhibits HIV-1 replication-potential effectiveness against most presently sequenced HIV-1 isolates. Nucleic Acids Res. 20:4581–4589 (1992).

    Google Scholar 

  145. M. Yu, J. O. Ojwang, O. Yamada, A. Hampel, J. Rapapport, D. Looney, and F. Wong-Staal. A hairpin ribozyme inhibits expression of diverse strains of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 90:6340–6344 (1993).

    Google Scholar 

  146. O. Yamada, M. Yu, J-K. Yee, G. Kraus, D. Looney, and F. Wong-Staal. Intracellular immunization of human T cells with a hairpin ribozyme against human immunodeficiency virus type 1. Gene Therapy 1:38–45 (1994).

    Google Scholar 

  147. W. Lange, E. M. Cantin, J. Finke, and G. Dölken. In vitro and in vivo effects of synthetic ribozymes targeted against BCR/ABL mRNA. Leukemia 7:1786–1794 (1993).

    Google Scholar 

  148. S. K. Shore, P. M. Nabissa, and E. P. Reddy. Ribozyme-mediated cleavage of the BCR/ABL oncogene transcript: in vitro cleavage of RNA and in vivo loss of P210 protein-kinase activity. Oncogene 8:3183–3188 (1993).

    Google Scholar 

  149. D. S. Snyder, Y. Wu, J. L. Wang, J. J. Rossi, P. Swiderski, B. E. Kaplan, and S. J. Forman. Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line. Blood 82:600–605 (1993).

    Google Scholar 

  150. W. Lange, M. Daskalakis, J. Finke, and G. Dölken. Comparison of different ribozymes for efficient and specific cleavage of BCR.ABL related mRNAs. FEBS Lett. 338:175–178 (1994).

    Google Scholar 

  151. M. Kashani-Sabet, T. Funato, T. Tone, L. Jiao, W. Wang, E. Yoshida, B. I. Hahfinn, T. Shitara, A. M. Wu, J. G. Moreno, S. T. Traweek, T. E. Ahlering, and K. J. Scanlon. Reversal of the malignant phenotype by an anti-ras ribozyme. Antisense Res. Dev. 2:3–15 (1992).

    Google Scholar 

  152. Y. Ohta, T. Tone, T. Shitara, T. Funato, L. Jiao, B. I. Kashfian, E. Yoshida, M. Horng, P. Tsai, K. Lauterbach, M. Kashani-Sabet, V. A. Florenes, O. Fodstad, and K. J. Scanlon. H-ras ribozyme-mediated alteration of the human melanoma phenotype. Annals New York Acad. Sci. 716:242–255 (1994).

    Google Scholar 

  153. P. M. Potter, L. C. Harris, J. S. Remack, C. C. Edwards, and T. P. Brent. Ribozyme-mediated modulation of human O6-methylguanine-DNA methyltransferase expression. Cancer Res. 53:1731–1734 (1993).

    Google Scholar 

  154. M. Sioud, J. B. Natvig, and Ø. Førre. Preformed ribozyme destroys tumour necrosis factor mRNA in human cells. J. Mol. Biol. 223:831–835 (1992).

    Google Scholar 

  155. P. L. Felgner, T. R. Gadek, M. Holm, R. Roman, W. Chan, M. Wenz, J. P. Northrop, G. M. Ringold, and M. Danielsen. Lipofection: A highly efficient lipid-mediated DNA-transfection procedure. Proc. Natl. Acad. Sci. USA 84:7413–7417 (1987).

    Google Scholar 

  156. J-P. Perreault, T. Wu, B. Cosineau, K. K. Ogilvie, and R. Cedergren. Mixed deoxy-and ribo-oligonucleotides with catalytic activity. Nature (London) 334:565–567 (1990).

    Google Scholar 

  157. N. R. Taylor, B. E. Kaplan, P. Swiderski, H. Li, and J. J. Rossi. Chimeric DNA-RNA hammerhead ribozymes have enhanced in vitro catalytic efficiency and increased stability in vivo. Nucleic Acids Res. 20:4559–4565 (1992).

    Google Scholar 

  158. P. Hendry, M. J. McCall, F. S. Santiago, and P. A. Jennings. A ribozyme with DNA in the hybridizing arms displays enhanced cleavage ability. Nucleic Acids Res. 20:5737–5741 (1992).

    Google Scholar 

  159. T. Shimayama, F. Nishikawa, S. Nishikawa, and K. Taira. Nuclease-resistant chimeric ribozymes containing deoxyribonucleotides and phosphorothioate linkages. Nucleic Acids Res. 21:2605–2611 (1993).

    Google Scholar 

  160. B. M. Chowrira and J. M. Burke. Extensive phosphorothioate substitution yields highly active and nuclease-resistant hairpin ribozymes. Nucleic Acids Res. 20:2835–2840 (1992).

    Google Scholar 

  161. R. A. Morgan and W. F. Anderson. Human gene therapy. Annu. Rev. Biochem. 62:191–217 (1993).

    Google Scholar 

  162. D. Castanotto, J. J. Rossi, and N. Sarver. Antisense catalytic RNAs as therapeutic agents. Advances in Pharmacol. 25:289–317 (1994).

    Google Scholar 

  163. M. Sioud and K. Drlica. Prevention of human immunodeficiency virus type 1 integrase expression in Escherichia coli by a ribozyme. Proc. Natl. Acad. Sci. USA 88:7303–7307 (1991).

    Google Scholar 

  164. D. Ding and H. D. Lipshitz. Localized RNAs and their functions. BioEssays 15:651–658 (1993).

    Google Scholar 

  165. B. A. Sellenger and T. R. Cech. Tethering ribozymes to a retroviral packaging signal for destruction of viral RNA. Science 262:1566–1569 (1993).

    Google Scholar 

  166. M. J. Fedor and O. C. Uhlenbeck. Substrate sequence effects on “hammerhead” RNA catalytic efficiency. Proc. Natl. Acad. Sci. USA. 87:1668–1672 (1990).

    Google Scholar 

  167. M. Zuker. Computer prediction of RNA structure. Methods Enzymol. 180:262–288 (1989).

    Google Scholar 

  168. R. B. Denman. Using RNAFOLD to predict the activity of small catalytic RNAs. BioTechniques 15:1090–1095 (1993).

    Google Scholar 

  169. S. J. Pachuk, K. Yoon, K. Moelling, and L. R. Coney. Selective cleavage of bcr-abl chimeric RNAs by a ribozyme targeted to non-contiguous sequences. Nucleic Acids Res. 22:301–307 (1994).

    Google Scholar 

  170. G. F. Joyce. Amplification, mutation, and selection of catalytic RNA. Gene 82:83–87 (1989).

    Google Scholar 

  171. D. L. Robertson and G. F. Joyce. Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA. Nature (London) 344:467–468 (1990).

    Google Scholar 

  172. A. A. Beaudry and G. F. Joyce. Directed evolution of an RNA enzyme. Science 257:635–641 (1992).

    Google Scholar 

  173. S. Joseph and J. M. Burke. Optimization of an anti-HIV hairpin ribozyme by in vitro selection. J. Biol. Chem. 268:24515–24518 (1993).

    Google Scholar 

  174. K. L. Nakamaye and F. Eckstein. AUA-cleaving hammerhead ribozymes: attempted selection for improved cleavage. Biochemistry 33:1271–1277 (1994).

    Google Scholar 

  175. H. Kobayashi, T. Dorai, J. Holland, and T. Ohnuma. Reversal of drug sensitivity in multidrug-resistant tumor cells by an MDR1 (PGY1) ribozyme. Cancer Res. 54:1271–1275 (1994).

    Google Scholar 

  176. J. W. Lamb and R. T. Hay. Ribozymes that cleave potato leafroll virus RNA within the coat protein and polymerase genes. J. General Virol. 71:2257–2264 (1990).

    Google Scholar 

  177. P. S. Chang, E. M. Cantin, J. A. Zaia, P. A. Ladne, D. A. Stephens, N. Sarver, and J. J. Rossi. Ribozyme-mediated site-specific cleavage of the HIV-1 genome. Clinical Biotech. 2:23–31 (1990).

    Google Scholar 

  178. E. U. Lorentzen, U. Wieland, J. E. Kuhn, and R. W. Braun. In vitro cleavage of HIV-1 vif RNA by a synthetic ribozyme. Virus Genes 5:17–23 (1991).

    Google Scholar 

  179. O. Heidenreich and F. Eckstein. Hammerhead ribozyme-mediated cleavage of the long terminal repeat RNA of human immunodeficiency virus type-1. J. Biol. Chem. 267:1904–1909 (1992).

    Google Scholar 

  180. M. Ventura, P. Wang, T. Ragot, M. Perricaudet, and S. Saragosti. Activation of HIV-specific ribozyme activity by self-cleavage. Nucleic Acids Res. 21:3249–3255 (1993).

    Google Scholar 

  181. R. B. Denman, B. Purow, R. Rubenstein, and D. L. Miller. Hammerhead ribozyme cleavage of hamster prior pre-mRNA in complex cell-free model systems. Biophys. Biochem. Res. Commun. 186:1171–1177 (1992).

    Google Scholar 

  182. F. von Weizsächer, H. E. Blum, and J. R. Wands. Cleavage of hepatitis B virus RNA by three ribozymes transcribed from a single RNA template. Biophys. Biochem. Res. Commun. 189:743–748 (1990).

    Google Scholar 

  183. Z. Xing and J. L. Whitton. Ribozymes which cleave arenavirus RNAs: Identification of susceptible target sites and inhibition by target site secondary structure. J. Virol. 66:1361–1369 (1992).

    Google Scholar 

  184. M. J. Bennett and J. V. Cullimore. Selective cleavage of closely-related mRNAs by synthetic ribozymes. Nucleic Acids Res. 20:831–837 (1992).

    Google Scholar 

  185. R. B. Denman. Cleavage of full-length βAPP mRNA by hammerhead ribozymes. Nucleic Acids Res. 21:4119–4125.

  186. H. Kobayashi, T. Dorai, J. Holland, and T. Ohnuma. Cleavage of human MDR1 mRNA by a hammerhead ribozyme. FEBS J. 319:71–74 (1993).

    Google Scholar 

  187. L. Wright, S. B. Wilson, S. Milliken, and P. Kearney. Ribozyme-mediated cleavage of the bcr/abl transcript in chronic myeloid leukemia. Exp. Haematol. 21:1714–1718 (1993).

    Google Scholar 

  188. Y. Kikuchi and N. Sasaki. Site-specific cleavage of natural mRNA sequences by newly designed hairpin catalytic RNAs. Nucleic Acids Res. 19:6751–6755 (1991).

    Google Scholar 

  189. A. Cornish-Bowden. Nomenclature for incompletely specified bases in nucleic acid sequences: Recommendations 1984. Nucleic Acids Res. 13:3021–3030 (1985).

    Google Scholar 

  190. R. A. Stull, L. A. Taylor, and F. C. Szoka, Jr. Predicting antisense oligonucleotide inhibitory efficacy: a computational approach using histograms and thermodynamic indices. Nucleic Acids Res. 20:3501–3508 (1992).

    Google Scholar 

  191. J. Han, Z. Zhu, C. Hsu, and W. H. Findley. Selection of antisense oligonucleotides on the basis of genomic frequency of the target sequence. Antisense Res. Devel. 4:53–65 (1994).

    Google Scholar 

  192. D. Chin, G. A. Green, G. Zon, F. C. Szoka Jr., and R. A. Straubinger. Rapid nuclear accumulation of injected oligodeoxynucleotides. The New Biologist 2:1091–1100 (1990).

    Google Scholar 

  193. J. P. Léonetti, N. Mechti, G. Degols, C. Gagnor, and B. Lebleu. Intracellular distribution of microinjected antisense oligonucle-otides. Proc. Natl. Acad. Sci. USA 88:2702–2706 (1991).

    Google Scholar 

  194. C. Mayfield and D. Miller. Effect of abasic linker substitution on triplex formation, Sp1 biding, and specificity in an oligonucleotide targeted to the human Ha-ras promoter. Nucleic Acids Res. 22:1909–1916 (1994).

    Google Scholar 

  195. H-J. Thiesen and C. Bach. Target detection assay (TDA): a versatile procedure to determine DNA binding sites as demonstrated on SP-1 protein. Nucleic Acids Res. 18:3203–3209 (1990).

    Google Scholar 

  196. G. Poste and R. Kirsh. Site-specific (targeted) drug delivery in cancer chemotherapy. Biotechnology 1:869–878 (1983).

    Google Scholar 

  197. F. Szoka. Liposomal drug delivery: current status and future prospects. In J. Wilschut and D. Hoekstra (eds.), Membrane Fusion, Marcel Dekker, New York, 1991, pp. 845–890.

    Google Scholar 

  198. J. Tsang and G. F. Joyce. Evolutionary optimization of the catalytic properties of a DNA-cleaving ribozyme. Biochemistry 35:5966–5973.

  199. J. M. Burke and A. Berzal-Harranz. In vitro selection and evolution of RNA; applications for catalytic RNA, molecular recognition, and drug discovery. FASEB J. 7:106–112 (1993).

    Google Scholar 

  200. A. Berzal-Herranz, S. Joseph, and J. M. Burke. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes and Devel. 6:129–134 (1992).

    Google Scholar 

  201. T. Friedmann. Progress toward human gene therapy. Science 244:1275–1281 (1989).

    Google Scholar 

  202. J. Haensler and F. C. Szoka, Jr. Gene transfer to cells: Reasons and Tools. D. Crommelin, P. Courvreur and D. Duchene (eds.) In Vitro and In Vivo Test Systems to Rationalize Drug Design and Delivery. Editions de Sante, Paris, 1994, pp. 150–170.

    Google Scholar 

  203. J. F. Milligan, R. J. Jones, B. C. Froehler, and M. D. Matteucci. Development of Antisense Therapeutics. Annals New York Academy of Sciences 666:228–241 (1994).

    Google Scholar 

  204. H. Schreier. The new frontier: gene and oligonucleotide therapy. Pharmaceutica Acta Helvetiae 68:145–59 (1994).

    Google Scholar 

  205. C. Chavany, T. Le Doan, P. Couvreur, F. Puisieux, and C. Hélène. Polyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides. Pharmaceutical Res. 9:441–449 (1992).

    Google Scholar 

  206. H. Maeda, L. W. Seymour, and Y. Miyamoto. Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chemistry, 3:351–362 (1992).

    Google Scholar 

  207. S. Joseph and J. M. Burke. Optimization of an anti-HIV hairpin ribozyme by in vitro selection. J. Biol. Chem. 268:24515–24518 (1993).

    Google Scholar 

  208. B. Chowrira and J. M. Burke. Binding and cleavage of nucleic acids by the “hairpin” ribozyme. Biochemistry 30:8518–8522 (1991).

    Google Scholar 

  209. B. M. Chowrira, A. Berzal-Herranz, and J. M. Burke. Ionic requirements for RNA binding, cleavage, and ligation by the hairpin ribozyme. Biochemistry 32:1088–1095 (1993).

    Google Scholar 

  210. B. M. Chowrira, Berzal-Herranz, C. F. Keller, and J. M. Burke. Four ribose 2′-hydroxyl groups essential for catalytic function of the hairpin ribozyme. J. Biol. Chem. 268:19458–19462 (1993).

    Google Scholar 

  211. S. E. Butcher and J. M. Burke. A photo-cross-likable tertiary structure motif found in functionally distinct RNA molecules is essential for catalytic function of the hairpin ribozyme. Biochemistry 33:992–999 (1994).

    Google Scholar 

  212. D. Herschlag, M. Khosla, Z. Tsuchihashi, and R. L. Karpel. An RNA chaperone activity of non-specific RNA binding proteins in hammerhead ribozyme catalysis. EMBO J. 13:2913–2924 (1994).

    Google Scholar 

  213. P. S. Holm, K. J. Scanlon, and M. Dietel. Reversion of multi-drug resistance in the P-glycoprotein-positive human pancreatic cell line (EPP85-181RDB) by introduction of a hammerhead ribozyme. Br. J. Cancer. 70:239–243 (1994).

    Google Scholar 

  214. F. Czubayko, A. T. Riegel, and A. Wellstein. Ribozyme-targeting elucidates a direct role of pleiotrophin in tumor growth. J. Biol. Chem. 269:21358–21363 (1994).

    Google Scholar 

  215. X-B. Tang, G. Hobom, and D. Luo. Ribozyme mediated destruction of influenza A virus in vitro and in vivo. J. Medical. Virol. 42:385–395 (1994).

    Google Scholar 

  216. S. Larsson, G. Hotchkiss, M. Andäng, T. Nyholm, J. Inzunza, I. Jansson, and L. Ährlund-Richter. Reduced β2-microglobulin mRNA levels in transgenic mice expressing a designed hammerhead ribozyme. Nucleic Acids Res. 22:2242–2248 (1994).

    Google Scholar 

  217. G. Baier, K. M. Coggeshall, G. Baier-Bitterlich, L. Giampa, D. Telford, E. Herbert, W. Shih, and A. Altman. Construction and characterization of lck-and fyn-specific tRNA:ribozyme chimeras. Molec. Immunol. 31:923–932 (1994).

    Google Scholar 

  218. D. N. Frank, M. E. Harris, and N. R. Pace. Rational design of self-cleaving pre-tRNA-ribonuclease P RNA conjugates. Biochemistry 33:10800–10808 (1994).

    Google Scholar 

  219. Boutorin, A. S., Gus'Kova, L. V., Ivanova, E. M., Kobetz, N. D., Zarytova, V. F., Ryte, A. S., Yurchenko, L. V., and Vlassov, V. V. (1989). Synthesis of alkylating oligonucleotide derivatives containing cholesterol or phenazinium residues at their 3′terminus and their interaction with DN within mammalian cells. FEBS Lett. 254:129–132.

    Google Scholar 

  220. Letsinger, R. L., Zhang, G., Sun, D. K., Ikeuchi, T., and Sarin, P. S. (1989). Cholesteryl-conjugated oligonucleotides: Synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture. Proc. Natl. Acad. Sci. USA 86:6553–6556.

    Google Scholar 

  221. Oberhauser, B., and Wagner, E. (1992). Effective incorporation of 2′-O-methyl-oligoribonucleotides and ehanced cell association through modification with thiocholesterol. Nucleic Acids Res. 20:533–538.

    Google Scholar 

  222. Shea, R. G., Marsters, J. C., and Biscgofberger, N. (1990). Sythesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates. Nucleic Acids Res. 18:3777–3783.

    Google Scholar 

  223. Kabanov, A. V., Vinogradov, S. V., Ovcharenko, A. V., Krivonos, A. V., Meliknubarov, N. S., Kiselev, V. I., and Severin, E. S. (1990). A new class of antivirals: Antisense oligonucleotides combined with a hydrophobic substitutent effectively inhibit influenza virus reproduction and synthesis of virus-specific proteins in MDCK cells. FEBS Lett. 259:327–330.

    Google Scholar 

  224. Pardridge, W. M., and Boado, R. J. (1991). Enhanced cellular uptake of biotinylated antisense oligonucleotide or peptide mediated by avidin, a cationic protein. FEBS Lett. 288:30–32.

    Google Scholar 

  225. Bonfils, E., Depierreux, C., Midoux, P., Thuong, N. T., Monsigny, M. and Roche, A. C. (1992a). Drug targeting: Synthesis and endocytosis of oligonucleotide-neoglycoprotein conjugates. Nucleic Acids Res. 20:4621–4629.

    Google Scholar 

  226. Lemaître, M., Bayard, B., and Lebleu, B. (1987). Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatits virus N protein mRNA initiation site. Proc. Natl. Acad. Sci. USA. 84:648–652.

    Google Scholar 

  227. Bunnell, B. A., Askari, F. K., and Wilson, J. M. (1992). Targeted delivery of antisense oligonucleotides by molecular conjugates. Somatic Cell Mol. Genetics. 18:559–569.

    Google Scholar 

  228. Léonetti, J. P., Machy, P., Degols, G., Lebleu, B., and Lesserman, L. (1990b). Antibody-targeted liposomes containing oligodeoxyribonucleotides complementary to viral RNA selectively inhibit viral replication. Proc. Natl. Acad. Sci. USA. 87:2448–2451.

    Google Scholar 

  229. Loke, S. L., Stein, C., Zhang, X. H., Avigan, M., Cohen, J. S., and Neckers, L. M. (1988). Delivery of c-myc antisense phosphorothioate oligodeoxynucleotides to hemapoietic cells in culture by liposome fusion: Specific reduction in c-myc protein expression correlated with inhibition of cell growth and DNA synthesis. Cur. Top. Microbiol. Immunol. 141:282–289.

    Google Scholar 

  230. S. Fawell, J. Seery, Y. Daikh, C. Moore, L. L. Chen, B. Pepinsky & J. Barsoum. Tat-mediated delivery of heterogeneous proteins into cells. Proc. Natl. Acad. Sci. U.S.A. 91:664–668, 1994.

    Google Scholar 

Download references

Authors
  1. Robert A. Stull
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis C. Szoka, Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stull, R.A., Szoka, Jr, F.C. Antigene, Ribozyme and Aptamer Nucleic Acid Drugs: Progress and Prospects. Pharm Res 12, 465–483 (1995). https://doi.org/10.1023/A:1016281324761

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016281324761

Search

Navigation