9-(4-Hydroxybutyl)-N2-phenylguanine (HBPG), a thymidine kinase inhibitor, suppresses herpes virus reactivation in mice.
In cells of the nervous system, which have little or no cellular thymidine kinase, the pharmacologic inhibition of viral thymidine kinase may prevent the reactivation of herpes virus, which requires phosphorylated thymidine for replication. We tested a newly synthesized inhibitor of viral thymidine kinase, 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG) for its capacity to suppress the reactivation of herpes simplex virus type 1 (HSV-1) in vivo. Mice, latently infected with McKrae strain HSV-1, were treated with intraperitoneal injections of HBPG in a corn oil vehicle (200 mg/kg every 3 h for a total of ten doses), and subjected to hyperthermic stress to stimulate viral reactivation immediately before the third treatment. Three h after the last treatment, the mice were sacrificed, and the presence of infectious virus was determined by culture of ocular surface swabs and trigeminal ganglionic homogenates. Additionally, viral DNA in ganglionic extracts was analyzed by quantitative PCR. Controls included latently infected, stressed animals receiving injections of corn oil vehicle only, and latently infected, drug- and vehicle-treated, unstressed animals. HBPG had a statistically significant inhibitory effect on hyperthermia-induced viral reactivation. Homogenates of trigeminal ganglia and ocular surface swabs from HBPG-treated animals were less likely to contain infectious virus than those of infected, vehicle-treated, stressed controls (P < 0.005, ANOVA). Unstressed controls showed no reactivation. Quantitation of viral DNA in ganglionic extracts demonstrated a 100-fold reduction in the amount of viral DNA in the ganglia of HBPG-treated animals, compared with vehicle-treated controls (P < 0.05, ANOVA). The results indicate that HBPG has an inhibitory effect when given systemically for the suppression of herpes virus reactivation in mice.
Gebhardt
B M
BM
Lions Eye Research Laboratories, LSU Eye Center, Louisiana State University Medical Center School of Medicine, New Orleans 70112, USA.
Wright
G E
GE
Xu
H
H
Focher
F
F
Spadari
S
S
Kaufman
H E
HE
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D005128:Eye Diseases / Q000821:virology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006561:Herpes Simplex / Q000188:drug therapy / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D012668:Trigeminal Ganglion / Q000821:virology; D014709:Vero Cells
C091724:9-(4-hydroxybutyl)-N(2)-phenylguanine; D004279:DNA, Viral; D006147:Guanine; D013937:Thymidine Kinase