Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function

Bioorg Med Chem. 2015 Nov 1;23(21):7095-109. doi: 10.1016/j.bmc.2015.09.002. Epub 2015 Sep 7.

Abstract

Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 μM.

Keywords: 1,4-Benzodiazepine; HIV-1 protease; HIV/AIDS; Protein–protein interaction; Proteomimetic; β-Hairpin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzodiazepines / chemistry
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology
  • Catalytic Domain
  • Cell Survival / drug effects
  • Drug Design
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / metabolism
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / enzymology
  • HIV-1 / physiology
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Protein Binding
  • Protein Structure, Secondary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • HIV Protease Inhibitors
  • Recombinant Proteins
  • Small Molecule Libraries
  • Benzodiazepines
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1