Mechanism of inhibition of human cytomegalovirus replication by oxetanocin G.

Abstract

Oxetanocin G(9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine, OXT-G) is a potent and selective agent against human cytomegalovirus (HCMV). In this study we synthesized the triphosphate form of OXT-G, OXT-GTP, and examined its effect on the activities of HCMV DNA polymerase, herpes simplex type 2 (HSV-2) DNA polymerase and human DNA polymerase alpha. OXT-GTP was found to inhibit all these polymerases in a competitive manner with respect to dGTP. The Km for dGTP and the Ki for OXT-GTP of HCMV DNA polymerase were 0.86 and 0.53 mu M, respectively, while the corresponding values of DNA polymerase alpha were 2.2 and 3.6 mu M, respectively. HPLC analysis using [3H]OXT-G also revealed that OXT-G was converted to its triphosphate form 7- to 8-fold more efficiently in HCMV-infected cells than in uninfected cells. The results suggest that both the preferential phosphorylation of OXT-G in HCMV-infected cells and the preferential inhibition of HCMV DNA polymerase by OXT-GTP may contribute towards the selective activity of OXT-G against HCMV replication.

• Authors: T Daikoku, N Yamamoto, S Saito, M Kitagawa, N Shimada, Y Nishiyama
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 176 Issue 2 Pg. 805-12 (Apr 30 1991) ISSN: 0006-291X [Print] United States
• PMID: 1851005 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• oxetanocin G
• oxetanocin guanosine triphosphate
• Guanine
• Guanosine Triphosphate
• DNA-Directed DNA Polymerase

Topics

• Antiviral Agents (pharmacology)
• Chromatography, High Pressure Liquid
• Cytomegalovirus (drug effects, enzymology, growth & development)
• DNA-Directed DNA Polymerase (metabolism)
• Fibroblasts (drug effects, physiology)
• Guanine (analogs & derivatives, pharmacology)
• Guanosine Triphosphate (analogs & derivatives, metabolism, pharmacology)
• Humans
• Phosphorylation
• Virus Replication (drug effects)