L-thymidine Is Phosphorylated by Herpes Simplex Virus Type 1 Thymidine Kinase and Inhibits Viral Growth

J Med Chem. 1992 Oct 30;35(22):4214-20. doi: 10.1021/jm00100a029.

Abstract

We have demonstrated that herpes simplex 1 (HSV1) thymidine kinase (TK) shows no stereospecificity for D- and L-beta-nucleosides. In vitro, L enantiomers are not recognized by human TK, but function as specific substrates for the viral enzyme in the order: L-thymidine (L-T) >> 2'-deoxy-L-guanosine (L-dG) > 2'-deoxy-L-uridine (L-dU) > 2'-deoxy-L-cytidine (L-dC) > 2'-deoxy- L-adenosine (L-dA). HSV1 TK phosphorylates both thymidine enantiomers to their corresponding monophosphates with identical efficiency and the Ki of L-T (2 microM) is almost identical to the Km for the natural substrate D-T (2.8 microM). The L enantiomer reduces the incorporation of exogenous [3H]T into cellular DNA in HeLa TK-/HSV1 TK+ but not in wild-type HeLa cells, without affecting RNA, protein synthesis, cell growth, and viability. L-T markedly reduces HSV1 multiplication in HeLa cells. Our observations could lead to the development of a novel class of antiviral drugs characterized by low toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Deoxyribonucleosides / chemical synthesis*
  • Deoxyribonucleosides / pharmacology
  • HeLa Cells
  • Humans
  • Leucine / metabolism
  • Simplexvirus / drug effects*
  • Simplexvirus / enzymology
  • Stereoisomerism
  • Thymidine / chemical synthesis
  • Thymidine / metabolism*
  • Thymidine / pharmacology*
  • Thymidine Kinase / antagonists & inhibitors*
  • Thymidine Kinase / metabolism
  • Uridine / metabolism

Substances

  • Deoxyribonucleosides
  • Thymidine Kinase
  • Leucine
  • Thymidine
  • Uridine