Inhibition of herpesvirus-induced thymidine kinase and DNA polymerase by beta-hydroxynorvaline

FEBS Lett. 1987 Oct 19;223(1):122-6. doi: 10.1016/0014-5793(87)80521-5.

Abstract

Treatment of HSV-infected cells with 5-10 mM beta-hydroxynorvaline (Hnv), a threonine analog, specifically affects herpesvirus DNA replication: both the rate of and total DNA synthesis are reduced, the former approximately 15-fold by Hnv (6 h post-infection) and the latter by 12-fold (between 3 and 12 h post-infection). The effect on DNA replication was due to inhibition of HSV-1 thymidine kinase (TK) and DNA polymerase (DP) activities; the former is reduced by 75% and whereas DP returns to baseline levels (when compared to untreated and/or uninfected cells). Host cell TK and DP activities are unaffected. It is suggested that beta-hydroxynorvaline is incorporated into these enzyme(s), either close to or at the active site thus perturbing viral DNA synthesis. beta-Hydroxynorvaline should have unique utility as a targeted antiviral compound, acting on both membrane-mediated phenomena (fusion, penetration and attachment) and DNA replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA, Viral / biosynthesis*
  • Nucleic Acid Synthesis Inhibitors*
  • Simplexvirus / enzymology*
  • Threonine / analogs & derivatives*
  • Threonine / pharmacology
  • Thymidine Kinase / antagonists & inhibitors*

Substances

  • DNA, Viral
  • Nucleic Acid Synthesis Inhibitors
  • 3-hydroxynorvaline
  • Threonine
  • Thymidine Kinase