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Peptides derived from HIV‐1 Rev inhibit HIV‐1 integrase in a shiftide mechanism
Author(s) -
Hayouka Zvi,
Rosenbluh Joseph,
Levin Aviad,
Maes Michal,
Loyter Abraham,
Friedler Assaf
Publication year - 2008
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20930
Subject(s) - integrase , tetramer , chemistry , peptide , dna , in vitro , dimer , biochemistry , fluorescence anisotropy , plasma protein binding , microbiology and biotechnology , enzyme , biology , organic chemistry , membrane
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. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 481–487, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com