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.