Mechanism of action and selectivity of acyclovir

Am J Med. 1982 Jul 20;73(1A):7-13. doi: 10.1016/0002-9343(82)90055-9.

Abstract

Acyclovir, an acrylic purine nucleoside analog, is a highly potent inhibitor of herpes simplex virus (HSV), types 1 and 2, and varicella zoster virus, and has extremely low toxicity for the normal host cells. This selectivity is due to the ability of these viruses to code for a viral thymidine kinase capable of phosphorylating acyclovir to a monophosphate; this capability is essentially absent in uninfected cells. The acyclovir monophosphate (acyclo-GMP) is subsequently converted to acyclovir triphosphate (acyclo-GTP) by cellular enzymes. Acyclo-GTP persists in HSV-infected cells for many hours after acyclovir is removed from the medium. The amounts of acyclo-GTP formed in HSV-infected cells are 40 to 100 times greater than in uninfected Vero cells. Acyclo-GTP acts as a more potent inhibitor of the viral DNA polymerases than of the cellular polymerases. The DNA polymerases of HSV-1 and HSV-2 also use acyclo-GTP as a substrate and incorporate acyclo-GMP into the DNA primer-template to a much greater extent than do the cellular enzymes. The viral DNA polymerase binds strongly to the acyclo-GMP-terminated template, and in thereby inactivated.

Publication types

  • Review

MeSH terms

  • Acyclovir
  • Animals
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Guanine / pharmacology
  • Humans
  • Nucleic Acid Synthesis Inhibitors*
  • Simplexvirus / drug effects*
  • Simplexvirus / enzymology
  • Thymidine Kinase / metabolism

Substances

  • Antiviral Agents
  • Nucleic Acid Synthesis Inhibitors
  • Guanine
  • acyclovir monophosphate
  • acyclovir triphosphate
  • Thymidine Kinase
  • Acyclovir