Nucleoside Analog Inhibitors of Hepatitis C Viral Replication: Recent Advances, Challenges and Trends

Future Med Chem. 2009 Nov;1(8):1429-52. doi: 10.4155/fmc.09.88.


Chronic hepatitis C virus (HCV) infection is a global health problem, with over 170 million people infected worldwide. The current therapy, pegylated interferon (PEG-IFN) plus ribavirin (RBV), provides only approximately a 40% sustained virological response (undetectable HCV RNA for greater than 24 weeks after cessation of therapy), in genotype 1-infected individuals. In addition to the limited sustained virological response, PEG-IFN/RBV treatment is associated with serious adverse effects. Nucleosides have long been the cornerstone of antiviral therapy because of their proven efficacy and high barrier to resistance. Through the use of surrogate viruses or the HCV subgenomic replicon, several classes of nucleoside analogs or their monophosphate prodrugs have been identified that inhibit HCV RNA replication. Nucleoside analogs that possess the 2´-C-methyl modification vary in their ability to be phosphorylated and to act as alternative substrate inhibitors of the HCV RNA polymerase. Herein, we discuss various classes of nucleoside inhibitors, with a focus on available structure-activity relationships, their mode of action and resistance profile.

Publication types

  • Review

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • Hepacivirus / drug effects*
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nucleosides / chemistry*
  • Nucleosides / metabolism
  • Ribavirin / therapeutic use
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects*


  • Antiviral Agents
  • NS-5 protein, hepatitis C virus
  • Nucleosides
  • Viral Nonstructural Proteins
  • Ribavirin