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Mode of action of (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine against herpesviruses.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 1995 Aug; Vol. 39 (8), pp. 1802-8. - Publication Year :
- 1995
-
Abstract
- The activity, metabolism, and mode of action of (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV) were studied. Compared to acyclovir (ACV), H2G has superior activity against VZV (50% inhibitory concentration of 2.3 microM) and Epstein-Barr virus (50% inhibitory concentration of 0.9 microM), comparable activity against HSV-1, and weaker activity against HSV-2. The antiviral effect on HSV-1 showed persistence after removal of compound. H2G was metabolized to its mono-, di- and triphosphate derivatives in virus-infected cells, with H2G-triphosphate being the predominant product. Only small amounts of H2G-triphosphate were detected in uninfected cells (1 to 10 pmol/10(6) cells), whereas the level in HSV-1-infected cells reached 1,900 pmol/10(6) cells. H2G was a substrate for all three viral thymidine kinases and could also be phosphorylated by mitochondrial deoxyguanosine kinase. The intracellular half-life of H2G-triphosphate varied in uninfected (2.5 h) and infected (HSV-1, 14 h; VZV, 3.7 h) cells but was always longer than the half-life of ACV-triphosphate (1 to 2 h). H2G-triphosphate inhibited HSV-1, HSV-2, and VZV DNA polymerases competitively with dGTP (Ki of 2.8, 2.2, and 0.3 microM, respectively) but could not replace dGTP as a substrate in a polymerase assay. H2G was not an obligate chain terminator but would only support limited DNA chain extension. Only very small amounts of radioactivity, which were too low to be identified by high-performance liquid chromatography analysis of the digested DNA, could be detected in purified DNA from uninfected cells incubated with [3H]H2G. Thus, H2G acts as an anti-herpesvirus agent, particularly potent against VZV, by formation of high concentrations of relatively stable H2G-triphosphate, which is a potent inhibitor of the viral DNA polymerases.
- Subjects :
- Antiviral Agents metabolism
Base Sequence
Cell Survival drug effects
Cells, Cultured
Chromatography, High Pressure Liquid
DNA, Viral analysis
Guanine metabolism
Guanine pharmacology
Herpesviridae enzymology
Herpesvirus 1, Human drug effects
Herpesvirus 1, Human enzymology
Herpesvirus 2, Human drug effects
Herpesvirus 2, Human enzymology
Herpesvirus 3, Human drug effects
Herpesvirus 3, Human enzymology
Humans
Kinetics
Molecular Sequence Data
Nucleic Acid Synthesis Inhibitors
Phosphorylation
Thymidine Kinase metabolism
Antiviral Agents pharmacology
Guanine analogs & derivatives
Herpesviridae drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 39
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 7486922
- Full Text :
- https://doi.org/10.1128/AAC.39.8.1802