Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) in animals

Abstract

The antiviral activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) was assessed in several animal models of herpes simplex virus (HSV) infection. BRL 39123 was as active as acyclovir (ACV) when applied topically to guinea pigs with a cutaneous HSV type 1 (HSV-1) infection and was also active topically in an HSV-2 genital infection. Before systemic administration to infected animals, BRL 39123 and ACV were administered orally and subcutaneously to mice, and the blood was assayed for each compound by high-pressure liquid chromatography. When given systemically to mice infected cutaneously with HSV-1, BRL 39123 was as active as ACV. In mice infected intranasally with HSV-1 or HSV-2, single daily subcutaneous doses of BRL 39123 were more effective than equivalent treatment with ACV, reflecting the more persistent activity seen in cell culture and a more stable triphosphate within the infected cell. When the compounds were supplied in drinking water for this infection, BRL 39123 and ACV had similar potencies against HSV-1, although ACV was more active against an HSV-2 infection than BRL 39123 was. In mice infected intraperitoneally with HSV-1, BRL 39123 was 10-fold more potent than ACV and a single dose of BRL 39123 reduced virus replication within the peritoneal cavity more effectively than 3 doses of ACV given 1, 5, and 20 h after infection. Although BRL 39123 failed to eradicate the virus from mice latently infected with HSV-1, treatment initiated 5 h after infection of the ear pinna reduced the numbers of mice that developed latent infections.The activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) against members of the herpesvirus family in cell culture has been described by Boyd et al. (4). In virus yield reduction assays, it was shown that BRL 39123 was more active than acyclovir (ACV) against herpes simplex virus type 1 (HSV-1) and of equal activity against HSV-2, although in plaque reduction assays BRL 39123 was less active than ACV against HSV-1 and HSV-2. It was demonstrated that treatment of HSV-infected MRC-5 cells with BRL 39123 for short periods inhibited virus replication much more effectively than similar treatment with ACV and that, in addition, virus replication remained depressed for prolonged periods after treatment with BRL 39123 (4). It was suggested that these results reflected different rates of phosphorylation for BRL 39123 and ACV and that the phosphorylated form of BRL 39123 was trapped efficiently within the infected cell.Since BRL 39123 is a potent inhibitor of HSV in vitro, the antiviral activity of this compound was studied in several animal models of HSV infection. Moreover, since cell culture studies showed that the continuous presence of BRL 39123 in the extracellular medium was not necessary for the maintenance of viral inhibition, it was predicted that persistent activity would be observed in infected animals. In this report, results of experiments are described in which BRL 39123 was tested for efficacy in several HSV infections in animals and i...

In vitro susceptibility of six isolates of equine herpesvirus 1 to acyclovir, ganciclovir, cidofovir, adefovir, PMEDAP and foscarnet

“…ganciclovir (Smith et al, 1983;Rollinson and White, 1983;Rollinson, 1987), three 2 0 -fluoropyrimidine nucleosides (Rollinson, 1987), (S)-9-[3-hydroxy-2-phosphonylmethoxypropyl]adenine or HPMPA (Field and Awan, 1990) and the HPMPA analogue cidofovir (Gibson et al, 1992). These compounds proved more effective than 9-[4-hydroxy-3-hydroxymethylbut-1-yl]guanine (Boyd et al, 1987) and penciclovir (de la Fuente et al, 1992). For acyclovir, contradictory data have been reported.…”

“…For acyclovir, contradictory data have been reported. Rollinson and White (1983) reported a 6-fold lower EC 50 than Boyd et al (1987). Further, based on comparison of EC 50 -values reported in literature, adefovir would be the least active compound in this series (Field and Awan, 1990).…”

Penciclovir-Resistance Mutations in the Herpes Simplex Virus DNA Polymerase Gene

“…Several HSV mutants known to contain ACV-resistance mutations in the pol gene have been examined for PCV susceptibility, but most have been reported to be as sensitive as their wild-type parents (Boyd et al, 1987;. To investigate further whether mutations in the HSV pol gene could confer altered sensitivity to PCV, we studied five drug-resistant mutants known or suspected to contain pol mutations.…”

“…Perkins, 1989;Hannah et al, 1989;Earnshaw et al, 1992;Vere Hodge and Cheng, 1993) have indicated that, like ACV and GCV, PCV is phosphorylated by the HSV thymidine kinase (TK) to the monophosphate. TK-deficient mutants are resistant to PCV (Larsson et al, 1986;Boyd et al, 1987;, indicating that phosphorylation by TK is critical for the selective antiviral activity of PCV. Once monophosphorylated, cellular enzymes can convert PCV monophosphate to its triphosphate.…”

“…Famciclovir is a prodrug with high oral availability, which is converted following absorption to its active form, penciclovir (PCV) (Vere known as carba-DHPG, 2'-carba-ganciclovir, 3HM-HBG and carba-2'NDG), like the earlier antiviral drugs aciclovir (ACV) and ganciclovir (GCV), is an acyclic guanosine analogue with activity against various herpesviruses (Tippie et el., 1984;Larsson et al, 1986;MacCoss et sl., 1986;Boyd et et., 1987). It can be considered to be a form of GCV in which the ether oxygen of the acyclic moiety has been converted to a methylene group (Fig.…”