Inhibitory effect of 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H - imidazole on HCMV DNA replication and permissive infection.
We found that Human Cytomegalovirus (HCMV) infection of human fibroblasts resulted in a dramatic increase in p38 mitogen-activated protein kinase (MAPK) phosphorylation. Recently, drug mediated inhibition of p38 has been demonstrated to exhibit anti-viral activity against HIV (Shapiro, L., Heidenreich, K.A., Meintzer, M.D. and Dinarello, C.A., 1998. Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro. Proc. Natl. Acad. Sci. USA. 95, 7422-7426). Therefore, we examined the effect of a specific p38 kinase inhibitor on HCMV infection. Inhibiting p38 activity in HCMV infected cells by treating cells with 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole; (FHPI), a p38 inhibitor drug, prevented permissive HCMV infection as measured by plaque assay. In the presence of FHPI, HCMV immediate early gene expression was slightly lower at early times of infection, but there was no inhibition of expression of the early gene UL-84, an HCMV protein essential for viral replication. However, FHPI inhibited HCMV DNA replication and late gene expression. The inhibitory effect of FHPI was reversible, as demonstrated by the induction of HCMV replication upon withdrawal of FHPI. Our data describes FHPI as a novel anti-HCMV compound that inhibits synthesis/activation of cellular and/or viral factors required for initiation of HCMV DNA replication.
D000998:Antiviral Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D017781:Genes, Immediate-Early / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D011725:Pyridines / Q000494:pharmacology*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases