Activities of benzimidazole D- and L-ribonucleosides in animal models of cytomegalovirus infections.
Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were implanted with human fetal tissue that was subsequently infected with HCMV. In one model, human fetal retinal tissue was implanted into the anterior chamber of the SCID mouse eye, and in the second, human fetal thymus and liver (thy/liv) tissues were implanted under the kidney capsule. After the implants were established, they were infected with 2,000 to 9,000 PFU of HCMV. To determine the efficacy of three benzimidazole nucleosides, 2-bromo-5,6-dichloro-(1-beta-D-ribofuranosyl)benzimidazole (BDCRB), GW275175X (175X), and GW257406X (1263W94, maribavir [MBV]) treatment was initiated 24 h after infection of the implants and continued for 28 days. Treatment consisted of either placebo, 25 mg of ganciclovir (GCV)/kg of body weight administered intraperitoneally (i.p.) twice daily, 33 or 100 mg of BDCRB/kg administered i.p. twice daily, or 75 mg of either MBV or 175X/kg administered orally twice daily. GCV was effective in both models, inhibiting HCMV infection by 5- to 3,000-fold. In the retinal tissue model, MBV and BDCRB reduced HCMV replication about fourfold through 21 days postinfection compared with results for the vehicle control. In the thy/liv tissue model, all three benzimidazole nucleosides were effective in inhibiting HCMV replication by approximately 30- to 3,000-fold in comparison to the vehicle control. These data indicate that the benzimidazole nucleosides were efficacious in these animal models and suggest that this class of compounds should be active against the various HCMV infections that occur in the immunocompromised host.
Kern
Earl R
ER
Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama 35233, USA. kern@uab.edu
Hartline
Caroll B
CB
Rybak
Rachel J
RJ
Drach
John C
JC
Townsend
Leroy B
LB
Biron
Karen K
KK
Bidanset
Deborah J
DJ
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D016513:Mice, SCID; D012160:Retina / Q000473:pathology / Q000821:virology; D012263:Ribonucleosides / Q000627:therapeutic use*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
D000998:Antiviral Agents; D001562:Benzimidazoles; D012263:Ribonucleosides; C109864:2-bromo-5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole; C486447:2-bromo-5,6-dichloro-1-ribopyranosyl-1H-benzimidazole; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole