title: The inhibitors of nucleotide biosynthesis leflunomide, FK778, and mycophenolic acid activate hepatitis B virus replication in vitro.
abstract: The inhibitors of pyrimidine synthesis, leflunomide and FK778, have been reported to exert broad antiviral effects, in addition to their immunosuppressive activities. Their possible therapeutic benefit for transplantation medicine is currently discussed, because they also block the replication of human cytomegalovirus and human polyomavirus BK, which both cause important complications in transplant recipients. Here, we show that leflunomide and FK778 strongly enhance hepatitis B virus (HBV) replication in vitro. This activity is shared by mycophenolic acid (MPA), an inhibitor of purine biosynthesis. Stimulation of HBV replication by these agents was linked to their inhibitory effects on de novo nucleotide biosynthesis because it could be efficiently counteracted by external nucleoside supply. Mechanistically, we found that mitogen-activated protein kinase p38 played a key role for the enhancement of HBV replication by leflunomide, FK778, and MPA. All three HBV-activating compounds increased p38 phosphorylation, in contrast to the HBV inhibitors, telbivudine and cyclosporine A. Moreover, silencing of p38 expression through RNA interference efficiently counteracted the stimulatory effect of leflunomide, FK778, and MPA on HBV replication.
  
  
  CONCLUSIONS
  Our data indicate that, in contrast to their reported inhibitory effects on other viruses, both leflunomide and FK778 can augment HBV replication. Treatment with leflunomide, FK778, or MPA may bear the risk to enhance HBV replication in infected patients.
authors.affiliation: Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Hoppe-Seyler
authors.forename: Peter
authors.initials: P
authors.lastname: Sauer
authors.forename: Claudia
authors.initials: C
authors.lastname: Lohrey
authors.forename: Felix
authors.initials: F
authors.lastname: Hoppe-Seyler
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D012367:RNA, Viral / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000480:Alkynes; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D012367:RNA, Viral; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D000077339:Leflunomide; D009173:Mycophenolic Acid