Dimerization inhibitors of HIV-1 protease based on a bicyclic guanidinium subunit

J Med Chem. 2003 Nov 20;46(24):5196-207. doi: 10.1021/jm030871u.


Original inhibitors of HIV-1 protease based on a chiral bicyclic guanidinium scaffold linked to short peptidic mimics of the terminal protease sequences and to a lipophilic group were designed. These inhibitors prevent dimerization of the native protease by an interfacial structure at the highly conserved antiparallel beta-strand involving both the N and C termini that substantially account for dimerization. The preorganized guanidinium spacer introduces additional electrostatic hydrogen-bonding interactions with the C-terminal Phe-99 carboxylate. Lipophilic residues linked to side chains and the guanidinium scaffold are essential for dimerization inhibition as ascertained by Zhang kinetics (4, K(id) = 290 nM; 6 or 6', K(id) = 150 nM; 8, K(id) = 400 nM) combined with a circular dichroism study on the enzyme thermal stability. Remarkably, less hydrophobic compounds result in mixed dimerization (1a and 3) or active site inhibitors (5). Removal of the guanidinium hydrophobic groups leads to less active or inactive ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Circular Dichroism
  • Dimerization
  • Guanidines / chemistry*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry*
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Models, Molecular
  • Protein Structure, Secondary
  • Serine / chemistry
  • Stereoisomerism
  • Tyrosine / chemistry


  • Bridged Bicyclo Compounds, Heterocyclic
  • Guanidines
  • HIV Protease Inhibitors
  • Tyrosine
  • Serine
  • HIV Protease