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. 1989 Nov 25;17(22):9341–9350. doi: 10.1093/nar/17.22.9341

Antiviral activity and possible mechanisms of action of oligonucleotides-poly(L-lysine) conjugates targeted to vesicular stomatitis virus mRNA and genomic RNA.

G Degols 1, J P Leonetti 1, C Gagnor 1, M Lemaitre 1, B Lebleu 1
PMCID: PMC335136  PMID: 2479915

Abstract

Synthetic oligonucleotides (oligomers) complementary to vesicular stomatitis virus (VSV) N protein mRNA have specific antiviral properties at concentrations lower than 1 microM when they are covalently linked to poly(L-lysine) (PLL). Since it is generally postulated that antisense oligomers act at the translational level, oligomers with potential targets on VSV viral mRNA and/or genomic RNA have been tested here. In vitro translation experiments in reticulocyte lysates, in vitro transcription experiments with permeabilized viruses, measurement of viral RNA transcription and accumulation in VSV infected cells, and antiviral experiments demonstrate in our model that antisense oligomers probably also act at other levels. Difficulties in the choice of the most effective antisense oligomer targets are also discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agris C. H., Blake K. R., Miller P. S., Reddy M. P., Ts'o P. O. Inhibition of vesicular stomatitis virus protein synthesis and infection by sequence-specific oligodeoxyribonucleoside methylphosphonates. Biochemistry. 1986 Oct 7;25(20):6268–6275. doi: 10.1021/bi00368a065. [DOI] [PubMed] [Google Scholar]
  2. Banerjee A. K. The transcription complex of vesicular stomatitis virus. Cell. 1987 Feb 13;48(3):363–364. doi: 10.1016/0092-8674(87)90184-x. [DOI] [PubMed] [Google Scholar]
  3. Blumberg B. M., Leppert M., Kolakofsky D. Interaction of VSV leader RNA and nucleocapsid protein may control VSV genome replication. Cell. 1981 Mar;23(3):837–845. doi: 10.1016/0092-8674(81)90448-7. [DOI] [PubMed] [Google Scholar]
  4. Gagnor C., Bertrand J. R., Thenet S., Lemaître M., Morvan F., Rayner B., Malvy C., Lebleu B., Imbach J. L., Paoletti C. alpha-DNA. VI: Comparative study of alpha- and beta-anomeric oligodeoxyribonucleotides in hybridization to mRNA and in cell free translation inhibition. Nucleic Acids Res. 1987 Dec 23;15(24):10419–10436. doi: 10.1093/nar/15.24.10419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Goodchild J., Carroll E., 3rd, Greenberg J. R. Inhibition of rabbit beta-globin synthesis by complementary oligonucleotides: identification of mRNA sites sensitive to inhibition. Arch Biochem Biophys. 1988 Jun;263(2):401–409. doi: 10.1016/0003-9861(88)90652-2. [DOI] [PubMed] [Google Scholar]
  6. Holt J. T., Redner R. L., Nienhuis A. W. An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation. Mol Cell Biol. 1988 Feb;8(2):963–973. doi: 10.1128/mcb.8.2.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  8. Lemaitre M., Bayard B., Lebleu B. Specific antiviral activity of a poly(L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site. Proc Natl Acad Sci U S A. 1987 Feb;84(3):648–652. doi: 10.1073/pnas.84.3.648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Leonetti J. P., Rayner B., Lemaitre M., Gagnor C., Milhaud P. G., Imbach J. L., Lebleu B. Antiviral activity of conjugates between poly(L-lysine) and synthetic oligodeoxyribonucleotides. Gene. 1988 Dec 10;72(1-2):323–332. doi: 10.1016/0378-1119(88)90159-x. [DOI] [PubMed] [Google Scholar]
  10. Liebhaber S. A., Cash F. E., Shakin S. H. Translationally associated helix-destabilizing activity in rabbit reticulocyte lysate. J Biol Chem. 1984 Dec 25;259(24):15597–15602. [PubMed] [Google Scholar]
  11. Matsukura M., Shinozuka K., Zon G., Mitsuya H., Reitz M., Cohen J. S., Broder S. Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7706–7710. doi: 10.1073/pnas.84.21.7706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Munroe S. H. Antisense RNA inhibits splicing of pre-mRNA in vitro. EMBO J. 1988 Aug;7(8):2523–2532. doi: 10.1002/j.1460-2075.1988.tb03100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Rose J. K., Lodish H. F., Brock M. L. Giant heterogeneous polyadenylic acid on vesicular stomatitis virus mRNA synthesized in vitro in the presence of S-adenosylhomocysteine. J Virol. 1977 Feb;21(2):683–693. doi: 10.1128/jvi.21.2.683-693.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Shen W. C., Ryser H. J. Conjugation of poly-L-lysine to albumin and horseradish peroxidase: a novel method of enhancing the cellular uptake of proteins. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1872–1876. doi: 10.1073/pnas.75.4.1872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Zamecnik P. C., Goodchild J., Taguchi Y., Sarin P. S. Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4143–4146. doi: 10.1073/pnas.83.12.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Zamecnik P. C., Stephenson M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978 Jan;75(1):280–284. doi: 10.1073/pnas.75.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Zerial A., Thuong N. T., Hélène C. Selective inhibition of the cytopathic effect of type A influenza viruses by oligodeoxynucleotides covalently linked to an intercalating agent. Nucleic Acids Res. 1987 Dec 10;15(23):9909–9919. doi: 10.1093/nar/15.23.9909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Zon G. Oligonucleotide analogues as potential chemotherapeutic agents. Pharm Res. 1988 Sep;5(9):539–549. doi: 10.1023/a:1015985728434. [DOI] [PubMed] [Google Scholar]
  19. van der Krol A. R., Mol J. N., Stuitje A. R. Modulation of eukaryotic gene expression by complementary RNA or DNA sequences. Biotechniques. 1988 Nov-Dec;6(10):958–976. [PubMed] [Google Scholar]

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