Abstract
Many antiretroviral agents have been designed to target the reverse transcriptase molecule. Most if not all of these compounds have, however, some degree of in vitro cytotoxicity and/or in vivo side effects. Selectivity of an antiviral compound depends, at least in part, on its enzyme specificity for inhibition (i.e., different effectiveness for reverse transcriptase and host cell DNA polymerases). The inhibitory effects of various compounds, thus far proven to suppress reverse transcriptase, on the cellular DNA polymerases α, β and γ were examined. Many of these reverse transcriptase inhibitors were found to be more or less inhibitory to the host cell DNA polymerases as well. The results obtained by parallel testing of antiretroviral agents for the inhibition of eukaryotic DNA polymerases provide useful information about the selectivity of the compounds. Such findings also foster the modification of drug structures for improvement of the efficacies of antiviral potentials.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Matsukage, A., Ono, K., Ohashi, A., Takahashi, T., Saneyoshi, M.: Inhibitory effect of 1-β-D-arabinofurano-sylthymine 5′-triphosphate and 1-β-D-arabinofurano-sylcytosine 5′-triphosphate on DNA polymerases from murine cells and oncornavirus. Cancer Research 1978, 38: 3076–3079.
Ono, K., Ohashi, A., Yamamoto, A., Matsukage, A., Takahashi, T., Saneyoshi, M., Ueda, T.: Inhibitory effects of 9-β-D-arabinofuranosylguanine 5′-triphosphate and 9-β-D-arabinofuranosyladenine 5′-triphosphate on DNA polymerases from murine cells and oncornavirus. Cancer Research 1979, 39: 4673–4680.
Smoler, D., Molineux, I., Baltimore, D.: Direction of polymerization by the avian myeloblastosis virus deoxyribonucleic acid polymerase. Journal of Biological Chemistry 1971, 246: 7697–7900.
Sundquist, B., Öberg, B.: Phosphonoformate inhibits reverse transcriptase. Journal of General Virology 1979, 45: 273–281.
De Clercq, E., Billiau, A., Hobbs, J., Torrence, P. F., Witkop, B.: Inhibition of oncornavirus functions by 2’-azido polynucleotides. Proceedings of the National-Academy of Sciences USA 1975, 72: 284–288.
DeClercq, E., Fukui, T., Kakiuchi, N., Ikehara, M., Hattori, M., Pfleiderer, W.: Influence of various 2- and 2′-substituted polyadenylic acids on murine leukemia virus reverse transcriptase. Cancer Letters 1979, 7: 23–37.
DeClercq, E., Billiau, A., Hattori, M., Ikehara, M.: Inhibition of oncornavirus functions by poly (2-methyl-thioinosinic acid). Nucleic Acids Research 1975, 2: 2305–2313.
Fukui, T., De Clercq, E.: Inhibition of murine leukemia virus reverse transcriptase by 2-halogenated polyadenylic acids. Biochemical Journal 1982, 203: 755–760.
Chermann, J.-C., Sinoussi, F., Jasmin, C.: Inhibition of RNA-dependent DNA polymerase of murine oncornavirus by ammonium-5-tungsto-2-antimoniate. Biochemical and Biophysical Research Communications 1975, 65: 1229–1236.
Dormont, D., Spire, B., Barré-Sinoussi, F., Montagnier, L., Chermann, J.-C.: Inhibition of RNA-dependent DNA polymerases of AIDS and SAIDS retroviruses by HPA-23 (ammonium-21-tungsto-9-antimoniate). Annales de l’Institut Pasteur/Virology 1985, 136: 75–84.
DeClercq, E.: Suramin: a potent inhibitor of reverse transcriptase of RNA tumor viruses. Cancer Letters 1979, 8: 9–22.
Ono, K., Nakane, H., Fukushima, M.: Differential inhibition of various deoxyribonucleic and ribonucleic acid polymerases by suramin. European Journal of Biochemistry 1988, 172: 349–353.
Modak, M. J.: Pyridoxal 5′ phosphate: a selective inhibitor of oncornaviral DNA polymerases. Biochemical and Biophysical Research Communications 1976, 71: 180–187.
Nakajima, K., Ono, K., Ito, Y.: Interconversion of molecular size of the DNA polymerase from Rauscher leukemia virus. Intervirology 1974, 3: 332–341.
Foley, G. E., Lazarus, H., Farber, S., Uzman, B. G., Boone, B. A., McCarthy, R. E.: Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer 1965, 18: 522–529.
Barré-Sinoussi, F., Chermann, J.-C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vézinet-Brun, F., Rouzioux, C., Rozenbaum, W., Montagnier, L.: Isolation of a T-lymphotropic retrovirus from a patient at a risk for acquired immune deficiency syndrome (AIDS). Science 1983, 220: 868–871.
Rey, M. A., Spire, B., Dormont, D., Barré-Sinoussi, F., Montagnier, L., Chermann, J.-C.: Characterization of the RNA-dependent DNA -dependent DNA polymerase of a new human T-lymphotropic retrovirus (lymphaden-opathy-associated virus). Biochemical and Biophysical Research Communications 1984, 121: 126–133.
Matsukage, A., Sivarajan, M., Wilson, S. H.: Studies on DNA α-polymerase of mouse myeloma: partial purification and comparison of three molecular forms of enzyme. Biochemistry 1976, 15: 5305–5314.
Matsukage, A., Bohn, E. W., Wilson, S. H.: On the DNA polymerase III of mouse myeloma: partial purification and characterization. Biochemistry 1975, 14: 1006–1020.
Ono, K., Ohashi, A., Tanabe, K., Matsukage, A., Nishi-zawa, M., Takahashi, T.: Unique requirements for template — primers of DNA polymerase β from rat ascites hepatoma AH130 cells. Nucleic Acids Research 1979, 7: 715–726.
Ono, K.: Discrimination of cellular and viral DNA polymerases in retrovirus-infected cells: principle and applications. Bulletin de l’Institut Pasteur 1987, 85: 3–35.
Lindell, T. J., Weinberg, F., Morris, P. W., Roeder, R. G., Rutter, W. J.: Specific inhibition of nuclear RNA polymerase II by α-amanitin. Science 1967, 170: 447–449.
Ono, K., Ogasawara, M., Matsukage, A.: Inhibition of the activity of DNA polymerase α by 2′, 3′-dideoxythymidine 5′-triphosphate. Biochemical and Biophysical Research Communications 1979, 88: 1255–1262.
Ono, K., Ogasawara, M., Iwata, Y., Nakane, H.: Inhibition of DNA polymerase α by 2′, 3′-dideoxyribonucleo-side 5′-triphosphates: effect of manganese ion. Bio-medicine & Pharmacotherapy 1984, 38: 382–389.
Ono, K., Ogasawara, M., Iwata, Y., Nakane, H., Fujii, T., Sawai, K., Saneyoshi, M.: Inhibition of reverse transcriptase activity by 2′, 3′-dideoxythymidine 5′-triphosphate and its derivatives modified on the 3′ position. Biochemical and Biophysical Research Communications 1986, 140: 498–507.
Atkinson, M. R., Deutcher, M. P., Kornberg, A., Russel, A. F., Moffat, J. G.: Enzymatic synthesis of deoxyribonucleic acid. XXXIV. Termination of chain growth by 2′, 3′-dideoxyribonucleotide. Biochemistry 1969, 8: 4897–4904.
Mitsuya, H., Broder, S.: Strategies for antiviral therapy in AIDS. Nature 1987, 325: 773–778.
Stenberg, K., Larsson, A.: Reversible effects on cellular metabolism and proliferation by trisodium phosphono-formate. Antimicrobial Agents and Chemotherapy 1978, 14: 727–730.
Balzarini, J., Mitsuya, H., De Clercq, E., Broder, S.: Comparative inhibitory effects of suramin and other selected compounds on the infectivity and replication of human T-cell lymphotropic virus (HTLV-III)/lym-phadenopathy-associated virus. International Journal of Cancer 1986, 37:451–457.
Jasmin, C., Chermann, J.-C., Herve, G., Teze, A., Souchay, P., Boy-Loustau, C., Raybaud, N., Sinoussi, F., Raynaud, M.: In vivo inhibition of murine leukemia and sarcoma viruses by the heteropolyanion 5-tungsto-2-antimoniate. Journal of National Cancer Institute 1974, 53: 469–474.
Tsiang, H., Atanasiu, P., Chermann, J.-C., Jasmin, C.: Inhibition of rabies virus in vitro by the ammonium-5-tungsto-2-antimoniate. Journal of General Virology 1978, 40: 665–668.
Rozenbaum, W., Dormont, D., Spire, B., Vilmer, E., Gentilini, M., Griscelli, C., Montagnier, L., Barré-Sinous-si, F., Chermann, J.-C.: Antimoniotungstate (HPA23) treatment of three patients with AIDS and one with prodrome. Lancet 1985, i: 450–451.
Ono, K., Nakane, H., Matsumoto, T., Barré-Sinoussi, F., Chermann, J.-C.: Inhibition of DNA polymerase α activity by ammonium 21-tungsto-9-antimoniate (HPA23). Nucleic Acids Research Symposium Series 1984, Number 15: 169–172.
Mitsuya, H., Popovic, M., Yarchoan, R., Matsushita, S., Gallo, R. C., Broder, S.: Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III. Science 1984, 226: 172–174.
Broder, S., Yarchoan, R., Collins, J. M., Lane, H. C., Markham, P. D., Klecker, R. W., Redfield, R. R., Mitsuya, H., Hoth, D. F., Gelmann, E., Groopman, J. E., Resnick, L., Gallo, R. C., Myers, C. E., Fauci, A. S.: Effects of suramin on HTLV-III/LAV infection presenting as Kaposi’s sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo. Lancet 1985, ii: 627–630.
Ono, K., Nakane, H., Barré-Sinoussi, F., Chermann, J.-C.: Differential inhibition of various mammalian DNA polymerase activities by ammonium 21-tungsto-9-antimoniate (HPA23). European Journal of Biochemistry 1988, in press.
Author information
Authors and Affiliations
Editor information
Rights and permissions
Copyright information
© 1989 Springer Fachmedien Wiesbaden
About this chapter
Cite this chapter
Ono, K. (1989). Mechanisms of Antoretroviral Compounds in Inhibition of Viral and Cellular DNA Polymerases. In: Jackson, G.G., Schlumberger, H.D., Zeiler, H.J. (eds) Perspectives in Antiinfective Therapy. Vieweg+Teubner Verlag, Wiesbaden. https://doi.org/10.1007/978-3-322-86064-4_8
Download citation
DOI: https://doi.org/10.1007/978-3-322-86064-4_8
Publisher Name: Vieweg+Teubner Verlag, Wiesbaden
Print ISBN: 978-3-528-07979-6
Online ISBN: 978-3-322-86064-4
eBook Packages: Springer Book Archive