Inhibitors of the protease from human immunodeficiency virus: design and modeling of a compound containing a dihydroxyethylene isostere insert with high binding affinity and effective antiviral activity

J Med Chem. 1991 Aug;34(8):2344-56. doi: 10.1021/jm00112a005.


The peptidomimetic template and the dihydroxyethylene isostere insert that were applied successfully to the design of renin inhibitors have been extended to the related protease from human immunodeficiency virus (HIV). The present report describes the structure-activity study leading to the identification of an inhibitor with a Ki of less than 1 nM for the HIV type-1 protease (compound II). This compound, containing a diol insert, is highly effective in blocking polyprotein processing in in vitro cell culture assays. Results obtained from kinetic analysis, studies of the stereochemistry of the insert, and modeling have led to insights as to the requisites involved in the active site-inhibitor interaction.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Binding Sites
  • Chemical Phenomena
  • Chemistry
  • Dipeptides / chemical synthesis
  • Drug Design*
  • HIV Protease / metabolism
  • HIV Protease Inhibitors*
  • HIV-1 / enzymology
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Protein Conformation
  • Structure-Activity Relationship
  • X-Ray Diffraction


  • Antiviral Agents
  • Dipeptides
  • HIV Protease Inhibitors
  • Oligopeptides
  • U 75875
  • MVT 101
  • N-(N-(N-(N-(1-naphthoxyacetyl)-histidyl)-5-amino-3,4-dihydroxy-2-isobutyl-7-methyloctanoyl)isoleucyl)-2-pyridylmethylamine
  • HIV Protease