Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based beta-strand mimics

J Org Chem. 2004 Sep 17;69(19):6185-201. doi: 10.1021/jo049288r.

Abstract

The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring beta-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.

MeSH terms

  • Binding Sites
  • Drug Design
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Mimicry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • NS3 protein, hepatitis C virus
  • Protease Inhibitors
  • Viral Nonstructural Proteins