Effective treatment of murine cytomegalovirus infections with methylenecyclopropane analogues of nucleosides.
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.
Rybak
R J
RJ
Department of Pediatrics, University of Alabama at Birmingham, 35294-2170, USA.
Zemlicka
J
J
Qiu
Y L
YL
Hartline
C B
CB
Kern
E R
ER
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000821:virology; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009705:Nucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D003521:Cyclopropanes; D009705:Nucleosides; C116544:synadenol; D000225:Adenine; D015774:Ganciclovir