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) ,ug/ml, respectively. Corresponding IC50s for ACV were 0.2, 0.6, and 3.8 ,ig/ml. Cytomegalovirus was relatively resistant to BRL 39123 (IC50, 51 ,ug/ml), but equid herpesvirus 1, bovid herpesvirus 2, and felid herpesvirus 1 were susceptible (IC50s, 1.6, 1.2, and 0.9 ,ug/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 ,ug/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 ,ug/mI, but at 300 ,ug/ml BRL 39123 was more inhibitory than ACV.Since the discovery of acyclovir (ACV) and its introduction as an effective treatment for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV) infections in humans, several laboratories have been searching for acyclic purine nucleosides with improved properties. ACV is a highly selective antiviral agent which is activated by the virus-induced thymidine kinase and inhibits susceptible viruses at concentrations which do not affect cell replication (9). Several other guanine derivatives have been described and evaluated as inhibitors of herpesviruses in cell culture and in animal infections (1,10,13,14,(22)(23)(24). Many publications show that 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) is beneficial in the treatment of severe cytomegalovirus (CMV) infections in humans, but because of adverse toxicity its use in less serious infections may be limited (20).Pandit et al. (18) first claimed to have synthesized 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine, but the compound was not fully characterized and no biological properties were given. The synthesis and isolation of pure compound have since been reported by Harnden and Jarvest (12), who found that the experimental conditions originally described provided a mixture of products. In the present paper, the activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123; Fig. 1

Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation

“…The concentration of 2-HM or acyclovir that produced a 50 % reduction in plaque numbers (ICs0 value) was determined ( Table 1). The ICs0 obtained for acyclovir against VZV in these assays was in agreement with results reported elsewhere using MRC5 cells (Boyd et al, 1987) and was similar to that observed for 2-HM. The appearance and stain uptake of cells was unaltered even with 80 ~tM-2-HM.…”

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance

“…15 Famciclovir was originally approved for the treatment of herpes simplex virus and herpes zoster virus. 16,17 Later, famciclovir was shown to have activity against human and duck hepatitis B viruses in enzymatic and cell culture assays and in animal models of infection. 15,[18][19][20][21] Clinical studies subsequently showed that famciclovir can reduce serum HBV levels in patients chronically infected with HBV.…”

Herpes simplex virus: Drug resistance and new treatment options using natural products (Review)

“…With the discovery of acyclovir (ACV) in 1974 (11) and later of penciclovir (PCV) (12), antiviral therapy was revolutionized. These guanine analogues are highly selective in fighting active HSV outbreaks because of their specific mode of action and activation.…”