Antiherpes effects and pharmacokinetic properties of 9-(4-hydroxybutyl) guanine and the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine

Abstract

Three acyclic guanosine analogs with similar structures, the (R) and (S) forms of 9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine, were compared for antiherpes activity in vivo and in vitro. The three guanosine analogs were viral thymidine kinase-dependent inhibitors of virus multiplication. In ceil cultures, (S)-9-(3,4-dihydroxybutyl)guanine was the least active of these three drugs against a variety of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains. This was also the case for a certain HSV-1 or HSV-2 strain in different cell lines, In cell cultures, (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine had similar antiherpes activities. However, in vivo in cutaneous HSV-1 infections in guinea pigs treated topically and in systemic HSV-2 infections in mice treated orally or intraperitoneally, only (R)-9-(3,4-dihydroxybutyl)guanine had a therapeutic effect. The extremely short half-life in plasma and the high clearance of 9-(4-hydroxybutyl)guanine as compared with those of (R)-9-(3,4-dihydroxybutyl)guanine probably made 9-(4-hydroxybutyl)guanine inefficacious when given intraperitoneally or orally to mice infected with herpesvirus. On the other hand, no kinetic differences between (R)-9-(3,4-dihydroxybutyl)guanine and 9-(4-hydroxybutyl)guanine were observed in penetration through guinea pig skin ex vivo, and no preferential metabolism of 9-(4-hydroxybutyl)guanine in skin was noted. We deduced that high thyntidine levels in guinea pig skin preferentially antagonize the antiviral effect of 9-(4-hydroxybutyl)guanine in cutaneous HSV-1 infections.The acyclic guanosine analogs 9-(4-hydroxybutyl)guanine (HBG) and 9-(3,4-dihydroxybutyl)guanine [(RS)-DHBG] (Fig. 1) are inhibitors of herpes simplex virus (HSV) replication in cell cultures (11,13,14). Their specificities are largely determined by selective phosphorylation to monophosphates by viral thymidine kinases. The compounds are poor substrates for cellular thymidine kinases. The antiviral effects of HBG and (RS)-DHBG coincide with a preferential inhibition of viral DNA synthesis in infected cells (11,13 (11)(12)(13)(14). The difference in phosphorylation rate is 7-fold for H4SV type 1 (HSV-1) thymidine kinase and 2.5-fold for HSV type 2 (HSV-2) thymidine kinase. Nevertheless, in inhibiting HSV-1 or HSV-2 replication in infected Vero cells, HBG and (RS)-DHBG have similar activities.In this study, we present a more extensive comparison of the antiviral effects in vitro and in vivo of HBG and the two enantiomeric forms of DHBG, (R)-DHBG and (S)-DHBG (Fig. 1)

Efficacy of the acyclic guanosine analog buciclovir [(R)-9-(3,4-dihydroxybutyl)guanine] in experimental genital herpes

“…We could not show a beneficial effect of intraperitoneal or oral administration of BCV to mice with HSV-2 genital infections, although intraperitoneal or oral treatment with BCV at one-tenth the dose used for genital infections very effectively prevented encephalitis caused by systemic HSV-2 infections in mice (2). In systemically infected mice, BCV inhibited virus replication in visceral organs and, therefore, the spread of virus to the central nervous system (2).…”

“…However, only BCV shows potent antiviral effects in vivo (2). These results emphasize the importance of evaluating the antiherpetic guanosine analogs in vivo.…”

“…HSV-2 strain MS was obtained from the American Type Culture Collection, Rockville, Md., and was propagated in Vero cells. The effects of BCV on replication of HSV-1 and HSV-2 in several cell lines have been described previously (2).…”

“…HSV-2 strain 91075 is a clinical isolate and was used in its third cell culture passage (2). HSV-2 strain MS was obtained from the American Type Culture Collection, Rockville, Md., and was propagated in Vero cells.…”

“…For topical use the drugs were suspended in the water-based cream used by Collins and Oliver (1) for ACV at concentrations of 5, 10, and 20% (wt/wt). The concentrations of BCV in serum were determined as previously described (2). The cream base without drug was used as placebo.…”