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. 1974 Jan;5(1):19–24. doi: 10.1128/aac.5.1.19

Sulfhydryl Reactivity: Mechanism of Action of Several Antiviral Compounds—Selenocystine, 4-(2-Propinyloxy)-β-Nitrostyrene, and Acetylaranotin

William Billard 1, Edwin Peets 1
PMCID: PMC428913  PMID: 4840446

Abstract

The addition of 5 mM dithiothreitol to a cell-free assay system for influenza ribonucleic acid (RNA) polymerase activity reverses the inhibitory activity otherwise possessed by three established antiviral compounds: selenocystine, 4-(2-propinyloxy)-β-nitrostyrene, and acetylaranotin. Although 50% or greater enzyme inhibitory activity is repeatedly achieved for these compounds at a concentration of approximately 50 μg/ml (0.1 to 0.25 mM) in the absence of dithiothreitol, no inhibition is seen in its presence at inhibitor concentrations as high as 200 μg/ml. Against the deoxyribonucleic acid-directed RNA polymerases of Escherichia coli and chicken embryo cells, acetylaranotin and 4-(2-propinyloxy)-β-nitrostyrene caused very little inhibition. Only selenocystine significantly inhibited these two enzymes in the absence of reducing agent, but to an extent substantially less than that obtained against the viral enzyme. These results appear to suggest that influenza RNA polymerase is uniquely sensitive to a variety of structurally diverse antiviral compounds as a consequence of their sulfhydryl reactivity—a fact which might aid in the search for and development of more potent chemotherapeutic agents.

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Selected References

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

  1. Cranston J. W., Ruddon R. W. The inhibition of ribonucleic acid polymerase from Escherichia coli by 6-chloro-8-aza-9-cyclopentylpurine. Mol Pharmacol. 1973 Jan;9(1):81–92. [PubMed] [Google Scholar]
  2. Hirschman S. Z. Inhibitors of viral nucleic acid transcriptases. Trans N Y Acad Sci. 1971 Jun;33(6):595–606. doi: 10.1111/j.2164-0947.1971.tb02625.x. [DOI] [PubMed] [Google Scholar]
  3. Ho P. P., Walters C. P. Specific inhibition of influenza virus-induced ribonucleic acid polymerase by gliotoxin. Antimicrob Agents Chemother (Bethesda) 1968;8:68–71. [PubMed] [Google Scholar]
  4. Ho P. P., Walters C. P., Streightoff F., Baker L. A., DeLong D. C. In vivo activity of an inhibitor of influenza virus-induced ribonucleic acid polymerase. Antimicrob Agents Chemother (Bethesda) 1967;7:636–641. doi: 10.1128/AAC.7.5.636. [DOI] [PubMed] [Google Scholar]
  5. Ishihama A., Hurwitz J. The role of deoxyribonucleic acid in ribonucleic acid synthesis. XVII. Multiple active sites of Escherichia coli ribonucleic acid polymerase. J Biol Chem. 1969 Dec 25;244(24):6680–6689. [PubMed] [Google Scholar]
  6. Knock F. E. Chromosomal residual protein-SH groups in cancer and gene control. Perspect Biol Med. 1967 Winter;10(2):310–313. doi: 10.1353/pbm.1967.0043. [DOI] [PubMed] [Google Scholar]
  7. Knock F. E., Galt R. M., Oester Y. T. Protein-sulfhydryl groups in cellular control mechanisms and cancer. J Am Geriatr Soc. 1967 Oct;15(10):882–899. doi: 10.1111/j.1532-5415.1967.tb02519.x. [DOI] [PubMed] [Google Scholar]
  8. Knock F. E., Galt R. M., Oester Y. T., Renaud O. V., Sylvester R. The use of selected sulfhydryl inhibitors in a preferential drug attack on cancer. Surg Gynecol Obstet. 1971 Sep;133(3):458–466. [PubMed] [Google Scholar]
  9. Knock F. E., Galt R. M., Oester Y. T., Sylvester R. Preferential inhibition of tumors by drug depressing DNA polymerases. JAMA. 1971 Nov 15;218(7):1049–1050. doi: 10.1001/jama.1971.03190200079024. [DOI] [PubMed] [Google Scholar]
  10. Larin N. M., Copping M. P., Herbst-Laier R. H., Roberts B., Wenham R. B. Antiviral activity of gliotoxin. Chemotherapy. 1965;10(1):12–23. doi: 10.1159/000220389. [DOI] [PubMed] [Google Scholar]
  11. Mahy B. W., Bromley P. A. In vitro product of a ribonucleic acid polymerase induced by influenza virus. J Virol. 1970 Sep;6(3):259–268. doi: 10.1128/jvi.6.3.259-268.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Miller P. A., Milstrey K. P., Trown P. W. Specific inhibition of viral ribonucleic acid replication by Gliotoxin. Science. 1968 Jan 26;159(3813):431–432. doi: 10.1126/science.159.3813.431. [DOI] [PubMed] [Google Scholar]
  13. Oki K., Hori K. Replication of viral nucleic acids. II. Inhibition of Q replicase by sulfhydryl-blocking reagents. Biochim Biophys Acta. 1972 Oct 11;281(2):233–243. [PubMed] [Google Scholar]
  14. Oxford J. S. An inhibitor of the particle-associated RNA-dependent RNA polymerase of influenza A and B viruses. J Gen Virol. 1973 Jan;18(1):11–19. doi: 10.1099/0022-1317-18-1-11. [DOI] [PubMed] [Google Scholar]
  15. RIGHTSEL W. A., SCHNEIDER H. G., SLOAN B. J., GRAF P. R., MILLER F. A., BARTZ O. R., EHRLICH J., DIXON G. J. ANTIVIRAL ACTIVITY OF GLIOTOXIN AND GLIOTOXIN ACETATE. Nature. 1964 Dec 26;204:1333–1334. doi: 10.1038/2041333b0. [DOI] [PubMed] [Google Scholar]
  16. Trown P. W. Antiviral activity of N, N'-dimethyl-epidithiapiperazinedione, a synthetic compound related to the gliotoxins, LL-S88alpha and beta, chetomin and the sporidesmins. Biochem Biophys Res Commun. 1968 Nov 8;33(3):402–407. doi: 10.1016/0006-291x(68)90585-8. [DOI] [PubMed] [Google Scholar]
  17. Trown P. W., Bilello J. A. Mechanism of action of gliotoxin: elimination of activity by sulfhydryl compounds. Antimicrob Agents Chemother. 1972 Oct;2(4):261–266. doi: 10.1128/aac.2.4.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Trown P. W., Lindh H. F., Milstrey K. P., Gallo V. M., Mayberry B. R., Lindsay H. L., Miller P. A. LL-S88-alpha, an antiviral substance produced by Aspergillus terreus. Antimicrob Agents Chemother (Bethesda) 1968;8:225–228. [PubMed] [Google Scholar]
  19. WEISBERGER A. S., SUHRLAND L. G. Studies on analogues of L-cysteine and L-cystine. II. The effect of selenium cystine on Murphy lymphosarcoma tumor cells in the rat. Blood. 1956 Jan;11(1):11–18. [PubMed] [Google Scholar]
  20. WEISBERGER A. S., SUHRLAND L. G. Studies on analogues of L-cysteine and L-cystine. III. The effect of selenium cystine on leukemia. Blood. 1956 Jan;11(1):19–30. [PubMed] [Google Scholar]
  21. Widnell C. C., Tata J. R. Studies on the stimulation by ammonium sulphate of the DNA-dependent RNA polymerase of isolated rat-liver nuclei. Biochim Biophys Acta. 1966 Sep;123(3):478–492. doi: 10.1016/0005-2787(66)90216-4. [DOI] [PubMed] [Google Scholar]
  22. Yamazaki Z., Totsuka A., Ohtaki K., Yamada Y. Antipoliovirus action of ethine compounds. Biochem Biophys Res Commun. 1970 Nov 9;41(3):723–730. doi: 10.1016/0006-291x(70)90073-2. [DOI] [PubMed] [Google Scholar]

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