Abstract
We studied the effects of selenazofurin alone and in combination with ribavirin on replication of influenza A and B viruses. These drugs showed little cytotoxicity as measured by leucine incorporation into protein in MDCK cells, although they were potent inhibitors of viral replication in the same cells. Selenazofurin inhibited growth of influenza A and B viruses at concentrations (50% inhibitory dose = 25 and 19 microM, respectively) which were similar to those at which growth was inhibited by ribavirin (50% inhibitory dose = 50 and 30 microM, respectively). The inhibition of replication of either influenza A or B virus was additive for any combination of ribavirin and selenazofurin. The effects of the 5'-triphosphate of selenazofurin on two replicative functions associated with the influenza virus RNA-dependent RNA polymerases, primer generation (initiation of transcription) and its subsequent elongation, were measured. Elongation was more sensitive to selenazofurin 5'-triphosphate than was primer generation, and the effects of this drug on these functions were approximately the same as those of ribavirin 5'-triphosphate. The activities of ribavirin triphosphate and selenazofurin triphosphate were additive, and combinations did not potentiate the individual inhibitory effects of these drugs on elongation.
Full text
PDF





Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berenbaum M. C. A method for testing for synergy with any number of agents. J Infect Dis. 1978 Feb;137(2):122–130. doi: 10.1093/infdis/137.2.122. [DOI] [PubMed] [Google Scholar]
- Chen T. R. In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain. Exp Cell Res. 1977 Feb;104(2):255–262. doi: 10.1016/0014-4827(77)90089-1. [DOI] [PubMed] [Google Scholar]
- Eriksson B., Helgstrand E., Johansson N. G., Larsson A., Misiorny A., Norén J. O., Philipson L., Stenberg K., Stening G., Stridh S. Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate. Antimicrob Agents Chemother. 1977 Jun;11(6):946–951. doi: 10.1128/aac.11.6.946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gebeyehu G., Marquez V. E., Van Cott A., Cooney D. A., Kelley J. A., Jayaram H. N., Ahluwalia G. S., Dion R. L., Wilson Y. A., Johns D. G. Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogues. Synthesis, structure, and interactions with IMP dehydrogenase. J Med Chem. 1985 Jan;28(1):99–105. doi: 10.1021/jm00379a018. [DOI] [PubMed] [Google Scholar]
- Huggins J. W., Robins R. K., Canonico P. G. Synergistic antiviral effects of ribavirin and the C-nucleoside analogs tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses. Antimicrob Agents Chemother. 1984 Oct;26(4):476–480. doi: 10.1128/aac.26.4.476. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jayaram H. N., Ahluwalia G. S., Dion R. L., Gebeyehu G., Marquez V. E., Kelley J. A., Robins R. K., Cooney D. A., Johns D. G. Conversion of 2-beta-D-ribofuranosylselenazole-4-carboxamide to an analogue of NAD with potent IMP dehydrogenase-inhibitory properties. Biochem Pharmacol. 1983 Sep 1;32(17):2633–2636. doi: 10.1016/0006-2952(83)90038-2. [DOI] [PubMed] [Google Scholar]
- Kilbourne E. D. Future influenza vaccines and the use of genetic recombinants. Bull World Health Organ. 1969;41(3):643–645. [PMC free article] [PubMed] [Google Scholar]
- Kirsi J. J., McKernan P. A., Burns N. J., 3rd, North J. A., Murray B. K., Robins R. K. Broad-spectrum synergistic antiviral activity of selenazofurin and ribavirin. Antimicrob Agents Chemother. 1984 Oct;26(4):466–475. doi: 10.1128/aac.26.4.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kirsi J. J., North J. A., McKernan P. A., Murray B. K., Canonico P. G., Huggins J. W., Srivastava P. C., Robins R. K. Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent. Antimicrob Agents Chemother. 1983 Sep;24(3):353–361. doi: 10.1128/aac.24.3.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knight V., McClung H. W., Wilson S. Z., Waters B. K., Quarles J. M., Cameron R. W., Greggs S. E., Zerwas J. M., Couch R. B. Ribavirin small-particle aerosol treatment of influenza. Lancet. 1981 Oct 31;2(8253):945–949. doi: 10.1016/s0140-6736(81)91152-1. [DOI] [PubMed] [Google Scholar]
- Lucas D. L., Robins R. K., Knight R. D., Wright D. G. Induced maturation of the human promyelocytic leukemia cell line, HL-60, by 2-beta-D-ribofuranosylselenazole-4-carboxamide. Biochem Biophys Res Commun. 1983 Sep 30;115(3):971–980. doi: 10.1016/s0006-291x(83)80030-8. [DOI] [PubMed] [Google Scholar]
- Plotch S. J., Bouloy M., Ulmanen I., Krug R. M. A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell. 1981 Mar;23(3):847–858. doi: 10.1016/0092-8674(81)90449-9. [DOI] [PubMed] [Google Scholar]
- Srivastava P. C., Robins R. K. Synthesis and antitumor activity of 2-beta-D-ribofuranosylselenazole-4- carboxamide and related derivatives. J Med Chem. 1983 Mar;26(3):445–448. doi: 10.1021/jm00357a024. [DOI] [PubMed] [Google Scholar]
- Streeter D. G., Witkowski J. T., Khare G. P., Sidwell R. W., Bauer R. J., Robins R. K., Simon L. N. Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci U S A. 1973 Apr;70(4):1174–1178. doi: 10.1073/pnas.70.4.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wray S. K., Gilbert B. E., Knight V. Effect of ribavirin triphosphate on primer generation and elongation during influenza virus transcription in vitro. Antiviral Res. 1985 Feb;5(1):39–48. doi: 10.1016/0166-3542(85)90013-0. [DOI] [PubMed] [Google Scholar]
- Wray S. K., Gilbert B. E., Noall M. W., Knight V. Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis. Antiviral Res. 1985 Feb;5(1):29–37. doi: 10.1016/0166-3542(85)90012-9. [DOI] [PubMed] [Google Scholar]
- Zimmerman T. P., Deeprose R. D. Metabolism of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide and related five-membered heterocycles to 5'-triphosphates in human blood and L5178Y cells. Biochem Pharmacol. 1978 Mar 1;27(5):709–716. doi: 10.1016/0006-2952(78)90508-7. [DOI] [PubMed] [Google Scholar]