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Papers In Press, published online ahead of print March 23, 2005
Department of Cell and Develomental Biology, Tel Aviv University, Tel Aviv, Ramat-Aviv
Corresponding Author: ahizy{at}post.tau.ac.il
Recent studies have shown that the integrase (IN) of human immunodeficiency virus type-1 (HIV-1) is inhibited in vitro by HIV-1 reverse transcriptase (RT). Now, we further investigate the specific protein sequences of RT that are involved in this inhibition by screening a complete library of RT-derived peptides for their inhibition of IN activities. Two 20-residues peptides, #4286, derived from the RT DNA-polymerase domain, and #4321 from the RT ribonuclease H domain, inhibit the enzymatic activities of IN, in vitro. The former peptide inhibits all three IN-associated activities (3'-end processing, strand transfer and disintegration), whereas the latter one inhibits primarily the first two functions. We show the importance of the sequences and peptide length for the effective inhibition of IN activities. Binding assays of the peptides to IN (with no DNA substrate present) indicate that the two inhibitory peptides (as well as several non-inhibitory peptides) interact directly with IN. Moreover, the isolated catalytic core domain of IN also interacts directly with the two inhibitory peptides. Nevertheless, only peptide #4286 can inhibit the disintegartion activity assoiated with the IN core domain, since this activity is the only one exhibited by this domain. This result was expected from the lack of inhibition of disintegration of full-length IN by peptide #4321. The data and the three-dimensional models presented suggest that the inhibition results from steric hindrance of the catalytic domain of IN. This information can substantially facilitate the development of novel drugs against HIV INs and, thus, contribute to the fight against AIDS.
J. Biol. Chem, 10.1074/jbc.M414679200
Submitted on December 30, 2004
Revised on March 17, 2005
Accepted on March 23, 2005
Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase
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