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 polymerase and that LBV phosphorylation can occur in the absence of viral factors including the UL97 protein kinase. Furthermore, LBV may be effective in the treatment of GCV-resistant HCMV.
Subject(s)
Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/metabolism , Cytomegalovirus/drug effects , Cytomegalovirus/enzymology , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Guanine/analogs & derivatives , Nucleic Acid Synthesis Inhibitors , Viral Proteins/antagonists & inhibitors , Cells, Cultured , Cytomegalovirus/metabolism , DNA Replication/drug effects , DNA, Viral/biosynthesis , DNA, Viral/drug effects , Drug Resistance, Microbial , Fibroblasts/metabolism , Fibroblasts/virology , Ganciclovir/pharmacology , Guanine/metabolism , Guanine/pharmacology , Humans , Phosphorylation , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
Foram tratados 95 pacientes portadores de varias dermatoses nas quais esta indicado o uso da crioterapia com nitrogenio liquido. Os autores chamam a atencao para a simplicidade do metodo utilizado e seu facil manuseio. Os resultados foram muito bons, sendo portanto a crioterapia um metodo bastante eficaz no controle destas afeccoes
