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Nucleotide Prodrugs for HCV Therapy

HCV infection is a significant worldwide health problem and is a major cause of hepatocellular carcinoma. The current standard of care, interferon and ribavirin, is only effective against a proportion of the patient population infected with HCV. To address the shortcomings of existing therapy, the development of direct acting antiviral agents is under investigation. The HCV RNA dependent RNA polymerase is an essential enzyme for viral replication and is therefore a logical target against which to develop novel anti-HCV agents. Nucleosides have been shown to be effective as antiviral agents for other viral diseases and therefore, have been investigated as inhibitors of HCV replication. The development of prodrugs of nucleoside 5′-monophosphates has been pursued to address limitations associated with poor nucleoside phosphorylation. This is required to produce the nucleoside 5′-triphosphate which is the anabolite that is the actual inhibitor of the polymerase enzyme. Prodrugs of nucleoside 5′-monophosphates have been developed that enable their delivery into cells and in vivo into the liver. The implementation of these prodrug strategies has ultimately led to the identification of several prodrugs of nucleoside 5′-monophosphates that are potent inhibitors of HCV replication in vitro. They have progressed into the clinic and the early data demonstrate greatly reduced viral load levels in HCV-infected patients. This review will survey the state of nucleotide prodrugs for the treatment of HCV.