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 r esulted in a dramatic increase in p38 mitogen-activated protein kinase (MAP K) phosphorylation. Recently, drug mediated inhibition of p38 has been demo nstrated to exhibit anti-viral activity against HIV (Shapiro, L., Heidenrei ch, K.A., Meintzer, M.D. and Dinarello, C.A., 1998. Role of p38 mitogen-act ivated 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 p 38 kinase inhibitor on HCMV infection. Inhibiting p38 activity in HCMV infe cted cells by treating cells with 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5- (4-pyridyl) 1H-imidazole; (FHPI), a p38 inhibitor drug, prevented permissiv e HCMV infection as measured by plaque assay. In the presence of FHPI, HCMV immediate early gene expression was slightly lower at early times of infec tion, 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 w as reversible, as demonstrated by the induction of HCMV replication upon wi thdrawal of FHPI. Our data describes FHPI as a novel anti-HCMV compound tha t inhibits synthesis/activation of cellular and/or viral factors required f or initiation of HCMV DNA replication. (C) 1999 Elsevier Science B.V. All r ights reserved.