Highly Potent and Selective Peptide-Based Inhibitors of the Hepatitis C Virus Serine Protease: Towards Smaller Inhibitors

Bioorg Med Chem Lett. 2000 Oct 16;10(20):2267-70. doi: 10.1016/s0960-894x(00)00465-0.

Abstract

Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cathepsin B / antagonists & inhibitors
  • Chymotrypsin / antagonists & inhibitors
  • Drug Design
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology*
  • Humans
  • Kinetics
  • Leukocyte Elastase / antagonists & inhibitors
  • Models, Molecular
  • Molecular Conformation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Pancreatic Elastase / antagonists & inhibitors
  • Protein Conformation
  • Serine Endopeptidases / metabolism
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Swine
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Oligopeptides
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Serine Endopeptidases
  • Chymotrypsin
  • Pancreatic Elastase
  • Leukocyte Elastase
  • Cathepsin B