PMID: 9420038Jan 7, 1998Paper

Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase

Antimicrobial Agents and Chemotherapy
D J TenneyR J Colonno

Abstract

Lobucavir (LBV) is a deoxyguanine nucleoside analog with broad-spectrum antiviral activity. LBV was previously shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. Here we determined the mechanism of action of LBV against human cytomegalovirus (HCMV). LBV inhibited HCMV DNA synthesis to a degree comparable to that of ganciclovir (GCV), a drug known to target the viral DNA polymerase. The expression of late proteins and RNA, dependent on viral DNA synthesis, was also inhibited by LBV. Immediate-early and early HCMV gene expression was unaffected, suggesting that LBV acts temporally coincident with HCMV DNA synthesis and not through cytotoxicity. In vitro, the triphosphate of LBV was a potent inhibitor of HCMV DNA polymerase with a Ki of 5 nM. LBV was phosphorylated to its triphosphate form intracellularly in both infected and uninfected cells, with phosphorylated metabolite levels two- to threefold higher in infected cells. GCV-resistant HCMV isolates, with deficient GCV phosphorylation due to mutations in the UL97 protein kinase, remained sensitive to LBV. Overall, these results suggest that LBV-triphosphate halts HCMV DNA replication by inhibiting the viral DNA polymeras...Continue Reading

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Citations

Nov 26, 1999·Antiviral Chemistry & Chemotherapy·A K Field
Jan 6, 1999·Archives of Pharmacal Research·J H HongC K Chu
Nov 9, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dorota G PiotrowskaJoanna Gotkowska
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Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·E De ClercqJ Neyts

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