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

Zvi Hayouka, Joseph Rosenbluh, Aviad Levin, Michal Maes, Abraham Loyter, Assaf Friedler

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30 Citations (Scopus)


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 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.

Original languageEnglish
Pages (from-to)481-487
Number of pages7
JournalBiopolymers (Peptide Science)
Issue number4
Publication statusPublished - 6 Oct 2008
Externally publishedYes


  • Drug design
  • HIV 1 integrase
  • HIV 1 Rev
  • Oligomerization equilibrium
  • Peptides

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