Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Authors:
  • TDTohru Daikoku
    Tohru Daikoku
  • YYYoshihiro Yoshida
    Yoshihiro Yoshida
  • MTMasaya Takemoto
    Masaya Takemoto
  • KOKumi Oshima
    Kumi Oshima
  • YEYoshito Eizuru
    Yoshito Eizuru
  • YKYoshinobu Kanda
    Yoshinobu Kanda
  • TMToshio Miyawaki
    Toshio Miyawaki
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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 EC50 for plaque inhibition of 12.0 μg/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 μg/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.

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