Fig. 6.

Mechanisms of action of nucleoside analog trifluridine (TFD, 4) and nucleotide analog prodrug adefovir dipivoxil (ADP, 5). (A) TFD is intracellularly converted into TFD-MP by cellular or viral thymidine kinase, followed by two additional phosphorylation steps to yield TFD-TP. The incorporation of TFD-TP by viral DNA polymerase terminates viral DNA (chain terminator). Alternatively, TFD-MP inhibits thymidylate synthase (TS) to stall the conversion of dUMP to dTMP, ultimately depleting the cellular dTTP pool (antimetabolite); (B) Ester prodrug ADP is intracellularly converted into adefovir first under the action of carboxylesterase (CES). The subsequent successive phosphorylation produces the active ADF-DP. When incorporated, ADF-DP terminates the viral DNA (chain terminator).