Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections

Abstract

We reported previously that purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against cytomegalovirus infection. A second-generation analog, (Z)-9-[[2,2-bis-(hydroxymethyl)cyclopropylidene]methyl]guanine (ZSM-I-62, cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV at 10 mg/kg of body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log10. In one HCMV model, human fetal retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than ganciclovir. These data indicate that the methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV infections in humans.

Figures

FIG. 1.

Structure of CPV.

FIG. 2.

Effect of oral treatment with CPV or GCV on replication of MCMV in BALB/c mice. Groups of mice were infected with MCMV and treated with either vehicle, 10 mg of GCV/kg, or 10 mg of CPV/kg. Three mice per group were euthanized on various days after infection, and lung, liver, spleen, kidney, pancreas, and salivary glands were removed and homogenized (10% [wt/vol]) for quantitation of virus. Titers of virus are expressed as log10 PFU/gram of tissue.

FIG. 3.

Effect of oral treatment with CPV or GCV on replication of MCMV in SCID mice. Groups of mice were infected with MCMV and treated with either vehicle, 10 mg of GCV/kg, or 10 mg of CPV/kg. Three mice per group were euthanized on various days after infection, and lung, liver, spleen, kidney, pancreas, and salivary glands were removed and homogenized (10% [wt/vol]) for quantitation of virus. Titers of virus are expressed as log10 PFU/gram of tissue.