Enzymatic basis for the selective inhibition of varicella zoster virus by 5 halogenated analogues of deoxycytidine

M. J. Dobersen, M. Jerkofsky, S. Greer

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

5 Bromodeoxycytidine (BrdC) and 5 iododeoxycytidine, at a concentration of 100 μg/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 molecular weight, calculated on the basis of the elution pattern on Sephadex G 150, is 70,000. Kinetic studies, demonstrating that dT and dC competitively inhibit the phosphorylation of BrdC, are consistent with the phosphorylation of these substrates at a common active site. Kinetic parameters include: K(i) dT = 0.6 μM; K(i) dC = 60 μM; K(m) BrdC = 8.5 μM. In contrast to its relatively high affinity for the VZ virus induced kinase, BrdC is a relatively poor substrate for the host kinases. Therefore, the basis for the selective inhibition of VZ virus by 5 halogenated analogues of dC is reflected in the induction of a pyrimidine deoxyribonucleoside kinase with a high affinity for BrdC.

Original languageEnglish (US)
Pages (from-to)478-486
Number of pages9
JournalJournal of virology
Volume20
Issue number2
DOIs
StatePublished - 1976

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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