Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design

J Med Chem. 2005 Aug 11;48(16):5088-91. doi: 10.1021/jm0489556.

Abstract

Hepatitis C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • DEAD-box RNA Helicases
  • Drug Design
  • Hepacivirus / enzymology*
  • Hydrogen Bonding
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / chemistry
  • Models, Molecular
  • Molecular Structure
  • Nucleoside-Triphosphatase
  • Peptides / chemistry*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protein Binding
  • Serine Endopeptidases
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Proteases

Substances

  • Antiviral Agents
  • Macrocyclic Compounds
  • Peptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • NS3 protein, hepatitis C virus
  • Serine Endopeptidases
  • Nucleoside-Triphosphatase
  • DEAD-box RNA Helicases
  • Viral Proteases