Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication in vitro

Abstract

Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is currently used as an immunosuppressive agent in kidney transplant recipients. After oral administration, MMF is hydrolysed to MPA, the active compound, which is a potent inhibitor of inosine monophosphate dehydrogenase (IMP-DH). Inhibition of this enzyme results in a depletion of the intracellular GTP and dGTP pools. MPA has been shown to inhibit the replication of a number of viruses, including arena viruses (Junin and Tacaribe), yellow fever virus, reovirus-1, parainfluenza-3 virus, Coxsackie B4 virus, Epstein-Barr virus and human immunodeficiency virus. To examine whether MPA also has an inhibitory effect on HBV replication, experiments were performed using cultures of primary human hepatocytes and HBV-transfected, HepG2 2.2.15 cells. After in vitro infection with HBV in human hepatocytes, HBV covalently-closed-circular (ccc) DNA and HBV mRNAs were detectable in the cells during the 10 days following infection. HBV DNA and hepatitis B surface antigen (HBsAg) were also secreted into the culture medium. In the presence of 10 microg ml-1 MPA (the therapeutic serum level of MPA as an immunosuppressive agent) in culture medium, HBV ccc DNA and HBV mRNAs became undetectable 5 days after treatment was started. The secretion of HBV DNA and HBsAg into the medium was also markedly reduced. No cytotoxic effect of the drug was noted during the experiments. The effect of MPA on HBV replication was abolished by the presence of guanosine (50 microg ml-1). In HepG2 2.2.15 cells (which contain an integrated tandem dimer of the HBV genome), MPA treatment had no significant inhibitory effect on the secretion of HBV DNA and HBsAg into the culture medium. HBV ccc DNA and HBV mRNAs in HepG2 2.2.15 cells were also not affected. The observed effect of MPA on HBV replication in primary human hepatocyte cultures may involve only episomal replication and may have clinical implications, especially before integration of HBV DNA into the host genome.

Inhibition of Reovirus by Mycophenolic Acid Is Associated with the M1 Genome Segment

“…As indicated earlier, MPA has been shown to inhibit replication of several viruses (20,24,30,37,38,45,47,48). However, viral factors, if any, that play a role(s) in sensitivity to MPA have not yet been delineated.…”

“…Inhibition of reovirus replication has been achieved with some antiviral compounds, including neplanocin A and some of its derivatives (18,52,58), acivicin (31), cicloxolone sodium (13), cyclopentenylcytosine (14,17), and ribavirin (another IMPDH inhibitor) (9,34,55). In an effort to characterize additional antiviral agents that could attenuate reovirus infection, MPA, a molecule that inhibits replication of other viruses (20,24,30,37,45), was assessed for its ability to inhibit T1L and T3D replication in mouse L929 fibroblasts. The dose response of MPA on the production of infectious viral progeny was determined for concentrations of MPA between 0 and 100 g/ml (Fig.…”

“…Currently, MPA is used clinically to prevent rejection of transplanted kidneys and hearts in combination with steroids and cyclosporine A (2,33,66). MPA can inhibit the replication of several viruses in vitro (20,24,30,37,38,45,47,48) and potentiates the inhibitory effects of acyclic guanosine analogs (such as acyclovir, penciclovir, and ganciclovir) against herpesviruses (47,48). MPA also potentiates the activity of nucleoside analogs against human immunodeficiency virus (27,28,38).…”

Hepatitis B reactivation after chemotherapy: two decades of clinical research

“…On the other hand, immunosuppressive agents may have a more direct stimulatory effect on viral replication. Exceptionally, one immunosuppressive agent, mycophenolate mofetil (MMF), has been shown to suppress the expression of HBsAg and HBeAg as well as the replication of HBV DNA in the 2.2.15 cell in a dosedependent manner [68,69]. In the transplant setting, steroids, azathioprine, cyclosporine, and tacrolimus (FK 506) are commonly used to prevent graft rejection.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…MPA was first observed to limit the cytopathic effects of VV, HSV and MV in cell culture 175 . Since then, the drug has been reported to inhibit the replication of Hantaan River virus, DENV, WNV, HBV, HEV, HCV, HIV and poxviruses by affecting viral nucleic acid synthesis [176][177][178][179][180][181][182] . In vivo MPA alone is not effective against HSV, but it has been shown to enhance the anti-HSV activities of acyclovir, gancyclovir and pencyclovir in experimental animals 183 .…”