Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: Insight into integrase–DNA complex formation and catalysis

Al-Mawsawi, Laith Q.; Christ, Frauke; Dayam, Raveendra; Debyser, Zeger; Neamati, Nouri

doi:10.1016/j.febslet.2008.02.076

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Volume 582, Issue 10 , Pages 1425-1430, 30 April 2008

Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: Insight into integrase–DNA complex formation and catalysis

Edited by Jacomine Krijnse-Locker

Laith Q. Al-Mawsawi
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
Frauke Christ
- The Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
Raveendra Dayam
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
Zeger Debyser
- The Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
Nouri Neamati
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Corresponding author. Fax: +1 323 442 1390.

Received 24 October 2007; received in revised form 18 February 2008; accepted 29 February 2008. published online 10 March 2008.

Abstract

A lens epithelium-derived growth factor (LEDGF)/p75 peptide was evaluated for human immunodeficiency virus type 1 integrase (IN) inhibitory activity. The LEDGF/p75 peptide modestly inhibited IN catalysis and was dependent on IN–DNA assembly. The peptide was also effective at disrupting LEDGF/p75–IN complex formation. We next investigated the activity of the LEDGF/p75 peptide on IN mutant proteins that are unable to catalyze the DNA strand transfer reaction. The LEDGF/p75 peptide displayed an increased potency on these IN proteins, from 5-fold to greater than 10-fold, indicating the IN multimeric state greatly influences the peptide inhibitory effects. These results shed light on IN–DNA multimeric formation, and how this process influences the LEDGF/p75–IN interaction.

Abbreviations: HIV-1, human immunodeficiency virus type 1, IN, integrase, WT, wild-type, LEDGF, lens epithelium-derived growth factor, IBD, integrase binding domain