Design, Synthesis, and Evaluation of Conformationally Constrained Tongs, New Inhibitors of HIV-1 Protease Dimerization

J Med Chem. 1999 Mar 25;42(6):957-62. doi: 10.1021/jm9803976.


The active form of human immunodeficiency virus type 1 protease (HIV-1 PR) is a homodimeric structure in which two subunits are linked through a two-stranded antiparallel beta-sheet consisting of the N- and C-termini of each monomer. To inhibit the dimerization process or disrupt the dimeric interface leading to inactive enzyme, conformationally constrained "molecular tongs" have been designed and synthesized to interfere with one monomer end in a beta-sheet fashion. These molecules are based on two peptidic strands attached to an aromatic scaffold. Inhibitions (submicromolar range) were obtained with molecular tongs containing tripeptidic or tetrapeptidic arms attached to a pyridinediol- or naphthalenediol-based scaffold (Kid = 0.56-4.5 microM at pH 4.7 and 30 degrees C). Kinetic studies are in agreement with an interface inhibition mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Dimerization
  • Drug Design
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Protein Structure, Secondary
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry


  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Naphthalenes
  • Oligopeptides
  • Pyridines
  • HIV Protease