Hepatitis C virus NS5B RNA-dependent RNA polymerase and host inosine monophosphate dehydrogenase (HCV NS5B and IMPDH)

The target complex consists of the Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) and the host cell enzyme inosine monophosphate dehydrogenase (IMPDH). NS5B is an RNA-dependent RNA polymerase (RdRp) essential for the replication of the HCV viral genome, as it synthesizes the complementary RNA strands required for viral proliferation (UniProt: P26663). IMPDH is a host enzyme that catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, which are necessary substrates for RNA synthesis (UniProt: P12268). Drugs like ribavirin exert their antiviral effects by interacting with both targets: ribavirin monophosphate inhibits host IMPDH to deplete intracellular GTP pools, while ribavirin triphosphate can be incorporated by NS5B into nascent viral RNA, leading to lethal mutagenesis or chain termination (PubMed: 15878357). While modern direct-acting antiviral (DAA) regimens focus heavily on highly specific NS5B inhibitors like sofosbuvir, the dual modulation of viral replication and host nucleotide metabolism remains a significant pharmacological strategy. Safety concerns associated with this target profile include ribavirin-induced hemolytic anemia and significant teratogenic risks. Monitoring of treatment efficacy is typically performed by measuring HCV RNA viral load and serum transaminase levels.

Other names

NS5B RNA-dependent RNA polymeraseRdRpInosine-5'-monophosphate dehydrogenaseIMPDHIMPDH1IMPDH2HCV polymeraseInosine monophosphate dehydrogenase

Inhibition of viral RNA-dependent RNA polymerase activity and depletion of intracellular guanosine triphosphate (GTP) pools through inhibition of de novo purine biosynthesis.