Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL 39123) in cell culture

Abstract

The activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against several herpesviruses was compared with that of acyclovir (ACV). In plaque reduction tests with clinical isolates of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus, mean 50% inhibitory concentrations (IC50S) (n = number tested) for BRL 39123 were 0.4 (n = 17), 1.5 (n = 13), and 3.1 (n = 5) micrograms/ml, respectively. Corresponding IC50S for ACV were 0.2, 0.6, and 3.8 micrograms/ml. Cytomegalovirus was relatively resistant to BRL 39123 (IC50, 51 micrograms/ml), but equid herpesvirus 1, bovid herpesvirus 2, and felid herpesvirus 1 were susceptible (IC50S, 1.6, 1.2, and 0.9 micrograms/ml, respectively). BRL 39123 was inactive against an HSV-1 strain which does not express thymidine kinase activity, but a DNA polymerase mutant selected for resistance to ACV was sensitive to BRL 39123 (IC50, 1.5 micrograms/ml). In contrast to the results from plaque reduction tests, BRL 39123 was more active than ACV against HSV-1 and of equal activity against HSV-2 in virus yield reduction assays in MRC-5 cells. After treatment of HSV-infected cultures for short periods, BRL 39123 was considerably more effective than ACV at reducing virus replication, and furthermore, after removal of extracellular BRL 39123, virus replication remained depressed for long periods, whereas such persistent activity was not observed with ACV. Neither compound significantly affected MRC-5 cell replication at 100 micrograms/ml, but at 300 micrograms/ml BRL 39123 was more inhibitory than ACV.