Peptides derived from HIV-1 Rev inhibit HIV-1 integrase in a shiftide mechanism

Biopolymers. 2008;90(4):481-7. doi: 10.1002/bip.20930.


The HIV-1 Integrase protein (IN) mediates the integration of the viral cDNA into the host genome. IN is an emerging target for anti-HIV drug design, and the first IN-inhibitor was recently approved by the FDA. We have developed a new approach for inhibiting IN by "shiftides": peptides derived from its cellular binding protein LEDGF/p75 that inhibit IN by shifting its oligomerization equilibrium from the active dimer to an inactive tetramer. In addition, we described two peptides derived from the HIV-1 Rev protein that interact with IN and inhibit its activity in vitro and in cells. In the current study, we show that the Rev-derived peptides also act as shiftides. Analytical gel filtration and cross-linking experiments showed that IN was dimeric when bound to the viral DNA, but tetrameric in the presence of the Rev-derived peptides. Fluorescence anisotropy studies revealed that the Rev-derived peptides inhibited the DNA binding of IN. The Rev-derived peptides inhibited IN catalytic activity in vitro in a concentration-dependent manner. Inhibition was much more significant when the peptides were added to free IN before it bound the viral DNA than when the peptides were added to a preformed IN-DNA complex. This confirms that the inhibition is due to the ability of the peptides to shift the oligomerization equilibrium of the free IN toward a tetramer that binds much weaker to the viral DNA. We conclude that protein-protein interactions of IN may serve as a general valuable source for shiftide design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Catalysis / drug effects
  • DNA, Viral / pharmacology
  • HIV Integrase / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Binding / drug effects
  • Protein Conformation / drug effects*
  • Protein Structure, Quaternary
  • Terminal Repeat Sequences / genetics
  • rev Gene Products, Human Immunodeficiency Virus / chemistry*


  • DNA, Viral
  • Peptides
  • rev Gene Products, Human Immunodeficiency Virus
  • rev protein, Human Immunodeficiency Virus-1
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1