L-FMAU. Anti-HBV, anti-EBV

L-FMAU is a potent anti-HBV nucleoside in 2.2.15 cells with a favorable toxicity profile in various cell lines in vitro. L-FMAU is phosphorylated to its monophosphate by cellular dCyd kinase, dThd kinase and mitochondrial dPyrd kinase. But cytosolic dThd kinase is the major enzyme responsible for its phosphorylation in these cells. The monophosphate is further phosphorylated to di- and triphosphate. The triphosphate inhibits HBV and EBV DNA polymerases, which appears to be the mechanism of L-FMAU as an antiviral agent. However, L-FMAU is not incorporated to HBV/EBV DNA. Interestingly, the major metabolite of L-FMAU in HBV containing cells is L-FMAUTP in comparison to LFMAUMP in EBV containing cells. Furthermore, the triphosphate does not interact with the cellular DNA polymerase α, β, δ and ε. This may explain the low toxicity of L-FMAU in vitro and in vivo. Pharmacokinetic studies in rats and woodchucks indicated that L-FMAU disposition is typical of nucleoside analogs. The compound is orally bioavailable in rats and woodchucks. Preliminary toxicity studies conducted in mice and woodchucks suggest that L-FMAU does not exhibit any marked toxicity in these animal models while D-FMAU showed significant toxicity. In vivo efficacy studies conducted in chronically infected woodchucks at 10 mg/day/kg for 50 weeks indicated that L-FMAU is a potent anti-HBV agent and no significant viral rebound was observed even after discontinuation of the drug. Therefore, potent in vitro and in vivo efficacy, favorable toxicity in animal models and various cell lines, as well as its unique structure, metabolism and mechanism make L-FMAU a potential clinical candidate as an anti-HBV agent.