synadenol and Cytomegalovirus-Infections

Emergence of drug-resistant human cytomegalovirus (HCMV) strains is a substantial problem during treatment of HCMV infections in immunocompromised patients. The Z-isomers of 2-hydroxymethylcyclopropylidenemethyl adenine (synadenol) and guanine (synguanol) were previously shown to be potent inhibitors of AD169 and Towne HCMV reference strains and postulated to share a common phosphorylation pathway with ganciclovir (GCV) possibly involving the UL97-encoded phosphotransferase. Analysis of synadenol and synguanol susceptibility of a series of HCMV isolates from immunocompromised untreated patients and from patients with treatment failure due to the emergence of GCV- and foscarnet (PFA)-resistant HCMV strains demonstrated that synadenol and synguanol are potent inhibitors of clinical HCMV isolates and are highly effective against both GCV- and PFA-resistant isolates. These results together with those showing resistance of a UL97 knock-out HCMV mutant to GCV as well as synadenol and synguanol suggest the involvement of UL97 phosphotransferase in synadenol and synguanol anabolism but with a substrate specificity different from that of GCV.

Topics: Adenine; Antiviral Agents; Cyclopropanes; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Foscarnet; Ganciclovir; Guanine; Humans; Immunocompromised Host; Phosphotransferases (Alcohol Group Acceptor)

A number of new nucleoside analogues with a Z- or E-methylenecyclopropane structure exhibited significant activity against human and murine cytomegaloviruses (HCMV, MCMV) in tissue culture that was generally comparable to, or greater than, 9-[(1-3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir, GCV). Several of these analogues were chosen for further evaluation of therapeutic efficacy utilizing a MCMV infection. Intraperitoneal (i.p.) inoculation of 3-week-old Balb/c mice with 2.0 x 10(5) plaque forming units (pfu) of MCMV results in an acute, lethal infection with rapid virus replication in visceral and glandular tissue, thus, making it an ideal model for identifying compounds that have potential for use in humans. Synadenol (QYL-284A) and synguanol (QYL-438) were administered i.p. once daily for 5 days initiated 6, 24, or 48 h post-viral infection. Significant protection was demonstrated at 50 and 16.7 mg/kg compared to placebo, with efficacy comparable to GCV. When delivered orally once or twice daily at 100 mg/kg per day, QYL-438 was active, but less effective than GCV. In addition, 2-amino-6-methoxypurine analogue (QYL-941) was active at 60 mg/kg administered orally twice daily, comparable to GCV, while it's prodrug (QYL-972) was as effective as GCV at 40 mg/kg when delivered twice daily for 5 days. Additionally, analogue 2-amino-6-cyclopropylaminopurine (QYL-769) was found to be highly efficacious when given orally twice daily for 5 days. Mortality of 0% and 13% was observed at 60 and 20 mg/kg, respectively, which was similar to GCV. Oral treatment with QYL-769 or GCV reduced virus replication in target organs, but neither resulted in complete clearance of MCMV. These data indicate that these new analogues have activity comparable to GCV when given orally to mice and should be evaluated further to assess their potential for use in humans.

Topics: Adenine; Administration, Oral; Animals; Antiviral Agents; Cells, Cultured; Cyclopropanes; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Mice; Mice, Inbred BALB C; Nucleosides; Viral Plaque Assay