Identification and characterization of a benzothiophene inhibitor of herpes simplex virus type 1 replication which acts at the immediate early stage of infection.
Analysis of a large compound library in a high throughput virus infection assay screen identified the benzothiophene PD146626 as a potent and specific inhibitor of herpes simplex virus type 1 (HSV-1) replication. PD146626 possessed an EC(50) and EC(90) against HSV-1 of 0.1 and 1 microM, respectively, and mediated no detectable cytotoxicity in cells at concentrations up to 1 microM. Western blot analyses and time of addition experiments demonstrated that in the presence of PD146626 HSV-1 underwent a specific block in viral gene expression at the immediate early stage. However, several observations indicated that a cellular function rather than a viral immediate early transactivator protein represented the molecular target for PD146626, including the lack of resistance of VP16 and ICP0 mutant viruses to the compound, the inability to select resistant strains of HSV-1 following exhaustive serial passaging of virus in the presence of the compound, and the sensitivity of human cytomegalovirus, which lacks VP16 and ICP0 homologs, to the compound. Moreover, kinetic studies suggested an unusual pattern of responsiveness of the host cell to PD146626, in that the compound could induce an extended antiviral state in cells after only a brief exposure. Together these results suggest that PD146626 targets a novel cellular function that is critical for the expression of HSV-1 immediate early genes but not host cell genes.
Boulware
S L
SL
Infectious Diseases Section, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Bronstein
J C
JC
Nordby
E C
EC
Weber
P C
PC
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D017781:Genes, Immediate-Early; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D017874:Immediate-Early Proteins; C435483:PD 146626; D013876:Thiophenes; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; C039447:glycoprotein D, Human herpesvirus 1; C048925:herpes simplex virus, type 1 protein ICP4; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1