Enzymatic basis for the selective inhibition of varicella-zoster virus by 5-halogenated analogues of deoxycytidine
- 1 November 1976
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 20 (2), 478-486
- https://doi.org/10.1128/jvi.20.2.478-486.1976
Abstract
5-Bromodeoxycytidine (BrdC) and 5-iododeoxycytidine, at a concentration of 100 .mu.g/ml, effectively inhibit the replication of varicella-zoster (VZ) virus in tissue culture. No toxicity could be demonstrated in uninfected cells under the same conditions. Studies on the enzymatic basis for this selective inhibition were undertaken. Infection of human embryonic lung cell monolayers with VZ virus-infected cells results in the induction of thymidine (dT), deoxycytidine (dC) and BrdC kinase activities (which are increased 10, 40 and 60-fold, respectively) and in a 70-fold stimulation in the incorporation of 3H nucleotide (5-bromodeoxyuridylate) derived from BrdC into DNA. The thermal stability of the VZ virus-induced activities differs significantly from the activities induced by herpes simplex virus type 1 and herpes simplex virus type 2 and those present in uninfected human embryonic lung cells. The VZ virus-induced dT, dC and BrdC kinase are similarly affected by temperature and cofractionate upon Sephadex gel filtration, findings consistent with the hypothesis that these activities are the function of a single enzyme: a pyrimidine deoxyribonucleoside kinase. The MW, calculated on the basis of the elution pattern on Sephadex G-150, is 70,000. Kinetic studies, demonstrating that dT and dC competively inhibit the phosphorylation of BrdC, are consistent with the phosphorylation of these substrates at a common active site. Kinetic parameters include Ki dT = 0.6 .mu.M; Ki dC = 60 .mu.M; Km BrdC = 8.5 .mu.M. In contrast to its relatively high affinity for the VZ virus-induced kinase, BrdC is a relatively poor substrate for the host kinases. The basis for the selective inhibition of VZ virus by 5-halogenated analogs of dC is reflected in the induction of a pyrimidine deoxyribonucleoside kinase with a high affinity for BrdC.This publication has 44 references indexed in Scilit:
- A simple cytochemical technique for demonstration of DNA in cells infected with mycoplasmas and virusesNature, 1975
- Deoxypyrimidine Kinases of Herpes Simplex Viruses Types 1 and 2: comparison of Serological and Structural PropertiesJournal of General Virology, 1975
- Cytosine Arabinoside for Localized Herpes Zoster in Patients with Cancer: Failure in a Controlled TrialThe Journal of Infectious Diseases, 1974
- Biochemical Studies on the Herpes Simplex Virus-specified Deoxypyrimidine Kinase ActivityJournal of General Virology, 1974
- Induction of Both Thymidine and Deoxycytidine Kinase Activity by Herpes VirusesJournal of General Virology, 1974
- Herpes Simplex Virus-specific Polypeptides Studied by Polyacrylamide Gel Electrophoresis of Immune PrecipitatesJournal of General Virology, 1974
- Inhibition of Deoxythymidine Kinase Activity by the Virostatic 5-Ethyl-2′-DeoxyuridineChemotherapy, 1973
- Deoxythymidine Kinase from Rabbit Kidney Cells Infected with Herpes Simplex Virus Types 1 and 2Intervirology, 1973
- Treatment of Zoster with Idoxuridine in Dimethyl Sulphoxide. Results of Two Double-blind Controlled TrialsBMJ, 1970
- INCORPORATION OF 5‐BROMODEOXYURIDINE AND 5‐IODODEOXYURIDINE INTO VIRAL DNA AND ITS EFFECT ON THE INFECTIVE PROCESS*Annals of the New York Academy of Sciences, 1965