Ribavirin and mycophenolic acid potentiate the activity of guanine- and diaminopurine-based nucleoside analogues against hepatitis B virus.
Mycophenolic acid [the active metabolite of the immunosuppressive agent mycophenolate mofetil (MMF)] and ribavirin were found to potentiate the anti-HBV activity of the guanine-based nucleoside analogues penciclovir (PCV), lobucavir (LBV) and 3'-fluorodideoxyguanosine (FLG) and diaminopurine dioxolane (DAPD). Ribavirin and mycophenolic acid are both inhibitors of inosine 5'-monophosphate dehydrogenase and cause a depletion of intracellular dGTP levels. It may be assumed that the 5'-triphosphorylated derivatives of the guanine-based nucleoside analogues, in the presence of reduced levels of dGTP, inhibit more efficiently the priming reaction as well as the reverse transcription and DNA-dependent DNA polymerase activity of the HBV polymerase. This assumption is corroborated by the observation that exogenously added guanosine reversed the potentiating effect of ribavirin and mycophenolic acid on the anti-HBV activity of the guanosine analogues. Our observations may have implications for those (liver) transplant recipients that receive MMF as (part of their) immunosuppressive regimen and that, because of de novo or persistent infection with HBV, need specific anti-HBV therapy.
Ying
C
C
Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
De Clercq
E
E
Neyts
J
J
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology; D004357:Drug Synergism; D000091344:Filaggrin Proteins; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006509:Hepatitis B / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011684:Purine Nucleosides / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D004148:Dioxolanes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D011684:Purine Nucleosides; D006151:Guanosine; C053539:penciclovir; D012254:Ribavirin; D006147:Guanine; C063638:lobucavir; C055315:3'-fluoro-2',3'-dideoxyguanosine; D009173:Mycophenolic Acid; D000212:Acyclovir