Molecular tongs containing amino acid mimetic fragments: new inhibitors of wild-type and mutated HIV-1 protease dimerization

J Med Chem. 2006 Jul 27;49(15):4657-64. doi: 10.1021/jm060576k.

Abstract

We have designed, synthesized, and evaluated the inhibitory activity and metabolic stability of new peptidomimetic molecular tongs based on a naphthalene scaffold for inhibiting HIV-1 protease dimerization. Peptidomimetic motifs were inserted into one peptidic strand to make it resistant to proteolysis. The peptidic character of the molecular tongs can be decreased without changing the way they inhibit dimerization. Mutated HIV-1 proteases are also vulnerable to dimerization inhibitors, and the multimutated protease ANAM-11 is twice as sensitive to the inhibitor compared to wild-type protease. Thus, the metabolic stability of antidimeric molecular tongs can be increased without compromising their ability to inhibit wild-type and mutated HIV-1 proteases in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Dimerization
  • Drug Stability
  • HIV Protease / chemical synthesis
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • Hydrolysis
  • Models, Molecular
  • Molecular Conformation
  • Molecular Mimicry
  • Mutation
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Peptides / chemistry
  • Pyridines / chemical synthesis
  • Pyridines / chemistry

Substances

  • Amino Acids
  • HIV Protease Inhibitors
  • Naphthalenes
  • Peptides
  • Pyridines
  • HIV Protease