title: Novel anticytomegalovirus activity of immunosuppressant mizoribine and its synergism with ganciclovir.
abstract: Cytomegalovirus (CMV) infection is a prominent infection in transplant recipients. The immunosuppressive drug mizoribine was shown to have anti-CMV activity in vitro and was reported to have an anti-CMV effect in renal transplantation. This study characterized the anti-CMV activity of mizoribine in vitro and its synergistic activity with ganciclovir. Mizoribine suppressed replication and at the EC(50) for plaque inhibition of 12.0 microg/ml. Mizoribine and ganciclovir exerted a strong synergism in anti-CMV activity. Mizoribine depletes guanosine nucleotides by inhibiting inosine monophosphate dehydrogenase and may increase the ratio of ganciclovir to guanosine in treated cells, resulting in a strong synergistic augmentation of the anti-CMV activity of ganciclovir. Two clinical isolates with UL97 mutations were less susceptible to mizoribine than the Towne strain but were equally susceptible in the presence of guanine. Two mizoribine-resistant strains were isolated after culture for 3 months with 100 microg/ml mizoribine, but they were as sensitive to ganciclovir as the parent Towne strain. The anti-CMV activity of mizoribine was antagonized by 2'-deoxyguanosine. Mizoribine inhibited CMV replication directly, and the sequence of mizoribine-resistant mutants of UL97 and UL54 was identical to that of the parent Towne strain, indicating the different anti-CMV action from ganciclovir, foscarnet, and maribavir. Mizoribine as an immunosuppressive and anti-CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir.
authors.affiliation: Department of Virology, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Daikoku
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Masaya
authors.initials: M
authors.lastname: Takemoto
authors.forename: Kumi
authors.initials: K
authors.lastname: Oshima
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Eizuru
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kanda
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000998:Antiviral Agents; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D015774:Ganciclovir / Q000494:pharmacology*; D006147:Guanine / Q000494:pharmacology; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009154:Mutation / Q000502:physiology; D012263:Ribonucleosides / Q000494:pharmacology*; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D006151:Guanosine; C010052:mizoribine; D006147:Guanine; D015774:Ganciclovir