Nucleotide prodrugs for HCV therapy.

摘要

HCV infection is a significant worldwide health problem and is a major cause ofhepatocellular carcinoma. The current standard of care, interferon and ribavirin,is only effective against a proportion of the patient population infected withHCV. To address the shortcomings of existing therapy, the development of directacting antiviral agents is under investigation. The HCV RNA dependent RNApolymerase is an essential enzyme for viral replication and is therefore alogical target against which to develop novel anti-HCV agents. Nucleosides havebeen shown to be effective as antiviral agents for other viral diseases andtherefore, have been investigated as inhibitors of HCV replication. Thedevelopment of prodrugs of nucleoside 5'-monophosphates has been pursued toaddress limitations associated with poor nucleoside phosphorylation. This isrequired to produce the nucleoside 5'-triphosphate which is the anabolite that isthe actual inhibitor of the polymerase enzyme. Prodrugs of nucleoside5'-monophosphates have been developed that enable their delivery into cells andin vivo into the liver. The implementation of these prodrug strategies hasultimately led to the identification of several prodrugs of nucleoside5'-monophosphates that are potent inhibitors of HCV replication in vitro. Theyhave progressed into the clinic and the early data demonstrate greatly reducedviral load levels in HCV-infected patients. This review will survey the state of nucleotide prodrugs for the treatment of HCV.