Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors

Bioorg Med Chem Lett. 2006 Jan 1;16(1):40-3. doi: 10.1016/j.bmcl.2005.09.049. Epub 2005 Oct 21.

Abstract

With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K(i)=5.8 microM). In general, we observe that interactions of P(2) side chain are more important than P(1) followed by P(3) and P(4). Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P(1) Arg is identified.

MeSH terms

  • Aldehydes / antagonists & inhibitors*
  • Binding, Competitive
  • Boronic Acids / chemistry
  • Chemistry, Pharmaceutical / methods*
  • Dengue Virus / enzymology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / pharmacology
  • Hydrogen Bonding
  • Ketones / chemistry
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / chemistry
  • Serine Endopeptidases / chemistry
  • Structure-Activity Relationship
  • Substrate Specificity
  • Time Factors
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry*

Substances

  • Aldehydes
  • Boronic Acids
  • Enzyme Inhibitors
  • Ketones
  • NS3 protein, flavivirus
  • Peptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Serine Endopeptidases
  • RNA Helicases