The immunosuppressive agent mycophenolate mofetil markedly potentiates the activity of lobucavir [1R(1alpha,2beta,3alpha)]-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine against different herpes viruses.
BACKGROUND
Mycophenolate mofetil (MMF) has been approved as an immunosuppressive agent in kidney transplant recipients and may thus be used concomitantly with antiherpetic agents, the latter for the treatment of intercurrent herpesvirus infections. The parent compound of MMF, mycophenolic acid (MPA), is a potent inhibitor of inosine monophosphate dehydrogenase and causes depletion of the intracellular (deoxy)guanosine triphosphate [(d)GTP] pools. Lobucavir [1R(1alpha,2beta,3alpha)]-9-[2,3-bis(hydroxymethyl)cyc lobutyl]guanine (LBV) is a novel antiviral agent with activity against ganciclovir-resistant cytomegalovirus (CMV) strains, that is in phase II clinical trials for the treatment of CMV infections. LBV triphosphate inhibits the viral DNA polymerase competitively with dGTP. We present the results of our studies on the antiviral effects of the combinations LBV + MMF and LBV + MPA.


METHODS
The antiviral effects of LBV either alone or in combination with MMF or MPA on the replication of CMV, herpes simplex virus type- (HSV) 1 (HSV-1), HSV-2, and thymidine kinase-deficient HSV-1 were studied by means of plaque or CPE reduction assays.


RESULTS
When combined with LBV, MPA (at concentrations ranging from 0.25 to 10 microg/ml, which are readily attainable in human plasma) markedly potentiated the antiviral efficacy of LBV against HSV-1 and HSV-2, that is a 10- to 100-fold decrease in EC50. Moreover, the EC50 of LBV against TK- HSV-1 decreased up to 1400-fold upon combination with MPA. MPA by itself had little or no effect on the replication of these viruses. Moreover, MPA and MMF resulted in a marked increase in the anti-CMV activity of LBV minimal FIC (FICmin: 0.24 and 0.26, respectively). Exogenously added guanosine reversed the potentiating effect of MPA on the antiviral activity of LBV, which indicates that this potentiating effect results from a depletion of the endogenous dGTP pools, thus favoring the inhibitory action of the LBV-triphosphate on the viral DNA polymerase. Ribavirin, another inhibitor of inosine monophosphate-dehydrogenase, also caused a marked enhancement of the antiviral activity of LBV against HSV-1 (12-fold), HSV-2 (20-fold), and TK- HSV-1 (25-fold).


CONCLUSIONS
MMF markedly potentiates the activity of LBV against HSV-1, HSV-2, TK- HSV-1, and CMV. This drug interaction may have important implications when using LBV in the treatment of intercurrent herpesvirus infections in transplant recipients under MMF therapy.
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D007166:Immunosuppressive Agents; D006147:Guanine; C063638:lobucavir; D009173:Mycophenolic Acid