Carbonylhydrazide-based molecular tongs inhibit wild-type and mutated HIV-1 protease dimerization

J Med Chem. 2012 Aug 9;55(15):6762-75. doi: 10.1021/jm300181j. Epub 2012 Jul 31.

Abstract

We have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel β-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K(id) of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Assays
  • Fluorometry
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • Hydrazines / chemical synthesis*
  • Hydrazines / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Pepsin A / antagonists & inhibitors
  • Pepsin A / chemistry
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Protein Multimerization
  • Renin / antagonists & inhibitors
  • Renin / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • HIV Protease Inhibitors
  • Hydrazines
  • Naphthalenes
  • Peptidomimetics
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • Pepsin A
  • Renin