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J. Biol. Chem., Vol. 280, Issue 23, 21987-21996, June 10, 2005

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Peptides Derived from the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 as Novel Inhibitors of the Viral Integrase^*

Iris Oz Gleenberg, Orna Avidan, Yehuda Goldgur¶, Alon Herschhorn, and Amnon Hizi||

From the Department of Cell and Developmental Biology, The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 and the ^¶Department of Chemistry, Ben Gurion University, Beer Sheva 84105, Israel

Recent studies have shown that the integrase (IN) of HIV-1 is inhibited in vitro by HIV-1 reverse transcriptase (RT). We further investigated the specific protein sequences of RT that were involved in this inhibition by screening a complete library of RT-derived peptides for their inhibition of IN activities. Two 20-residue peptides, peptide 4286, derived from the RT DNA polymerase domain, and the one designated 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 showed 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) indicated 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 interacted directly with the two inhibitory peptides. Nevertheless, only peptide 4286 can inhibit the disintegration activity associated with the IN core domain, because 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 suggested that the inhibition resulted 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.

Received for publication, December 30, 2004 , and in revised form, March 17, 2005.

^* This work was supported by Grant 405/02 from the Israel Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains sequences of all studied peptides.

Performed this work in partial fulfillment of a Ph.D. thesis at Tel Aviv University.

^|| Incumbent of The Gregorio and Dora Shapira Chair for the Research of Malignancies. To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: 972-36409974; Fax: 972-36407432; E-mail: ahizy{at}post.tau.ac.il.

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