Effects of protein tyrosine kinase inhibitors on the replication of herpes simplex virus and the phosphorylation of viral proteins.
The effect of protein tyrosine kinase (PTK) inhibitors on the replication of herpes simplex virus (HSV) was examined. Tyrphostins AG17, AG213, AG490, and AG555, and herbimycin A all inhibited the plaque formation of HSV type 1 (HSV-1) in Vero cells, but AG17, AG490, and AG555 exhibited a more selective antiviral effect. In the presence of 0.4 microM AG17, the virus production 24 h after infection was decreased to 7.7% of the untreated control level. Even if the treatment was started 12 h after the initiation of infection, the viral titer was reduced by 82.4%, compared with the untreated control level. In HSV-1-infected cells ICPs 6, 17/18, 19/20, and 25 were tyrosine-phosphorylated proteins. The synthesis and phosphorylation of these proteins were inhibited by AG17, and suppression of ICP 19/20, which were identified as the UL47 gene products, was the greatest. In contrast, the in vitro autophosphorylation of viral proteins was not affected by this PTK inhibitor. These results indicate that tyrphostin may represent a novel class of inhibitors of HSV-1, and that the viral proteins which have phosphorylated tyrosine residues and are suppressed by AG17 most significantly are the products of the UL47 gene, the tegument proteins VP13/14.
Yura
Y
Y
Second Department of oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Japan.
Kusaka
J
J
Tsujimoto
H
H
Yoshioka
Y
Y
Yoshida
H
H
Sato
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016227:Benzoquinones; D002396:Catechols / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D018139:Simplexvirus / Q000378:metabolism / Q000502:physiology*; D020032:Tyrphostins; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000032:analysis; D014764:Viral Proteins / Q000096:biosynthesis / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016227:Benzoquinones; D002396:Catechols; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D009570:Nitriles; D010636:Phenols; D011809:Quinones; D020032:Tyrphostins; C085822:VP13-14 protein, herpes simplex virus type 1; D014760:Viral Fusion Proteins; D014764:Viral Proteins; C060152:tyrphostin 47; D017828:Rifabutin; C001784:SF 6847; C020754:herbimycin; D011505:Protein-Tyrosine Kinases