Target intelligence / Profile preview

Non-structural protein 5B, hepatitis C virus (NS5B)

Target
NS5B
Molecular classification
Enzyme, RNA-dependent RNA polymerase, Viral non-structural protein
01

Overview

Non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) genome. It is an essential viral enzyme responsible for replication of the positive-strand viral RNA and is localized near the endoplasmic reticulum as part of the replication complex. Structurally, NS5B shows a typical right-hand polymerase architecture with finger, palm, and thumb domains, and catalyzes RNA synthesis de novo. Because this function is unique and not present in mammalian cells, NS5B is an attractive and validated target for direct-acting antiviral (DAA) drugs against HCV, with both nucleoside and non-nucleoside inhibitors clinically approved and in development. NS5B also interacts with other HCV proteins and cellular factors, playing roles in viral genome replication, assembly, and possibly morphogenesis[1][2][3][4][5].

Other names
NS5BHCV RNA-dependent RNA polymeraseHepatitis C virus polymeraseHCV NS5B
02

Mechanism of action

Inhibition of RNA-dependent RNA polymerase activity, blocking replication of viral RNA (nucleoside analogues act as chain terminators, non-nucleoside inhibitors bind allosteric sites and inhibit polymerase function)[2][4]

03

Biological functions

Viral RNA replicationAssembly of viral replicase complexesParticipation in virus morphogenesis
04

Disease associations

Infection (specifically, hepatitis C virus infection)Liver fibrosis, cirrhosis, hepatocellular carcinoma (due to chronic HCV infection)[2][3]
05

Safety considerations

Emergence of drug resistance mutations (notably S282T for nucleoside inhibitors)Potential off-target cytotoxicity with some compounds[2][4]Hepatic side effects due to failure of viral clearance or persistence of infected hepatocytes
06

Interacting drugs

Sofosbuvir (a nucleoside analogue inhibitor)

2 more in the full profile.

07

Biomarkers

HCV RNA levels (as a pharmacodynamic biomarker of NS5B inhibitor efficacy in patients)

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