Ying C, De Clercq E, Neyts J
Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
Antiviral Res. 2000 Nov;48(2):117-24. doi: 10.1016/s0166-3542(00)00121-2.
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.
霉酚酸[免疫抑制剂霉酚酸酯（MMF）的活性代谢产物]和利巴韦林被发现可增强鸟嘌呤核苷类似物喷昔洛韦（PCV）、洛布卡韦（LBV）、3'-氟脱氧鸟苷（FLG）和二氨基嘌呤二氧戊环（DAPD）的抗乙肝病毒活性。利巴韦林和霉酚酸都是肌苷5'-单磷酸脱氢酶的抑制剂，可导致细胞内dGTP水平降低。可以推测，在dGTP水平降低的情况下，鸟嘌呤核苷类似物的5'-三磷酸化衍生物能更有效地抑制引发反应以及乙肝病毒聚合酶的逆转录和依赖DNA的DNA聚合酶活性。这一推测得到了以下观察结果的确证：外源性添加鸟苷可逆转利巴韦林和霉酚酸对鸟苷类似物抗乙肝病毒活性的增强作用。我们的观察结果可能对那些接受MMF作为免疫抑制方案（一部分）的（肝脏）移植受者有影响，这些受者因新发或持续性乙肝病毒感染而需要特异性抗乙肝病毒治疗。
