title: Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370.
abstract: The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem 91904, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.forename: Aviad
authors.initials: A
authors.lastname: Levin
authors.forename: Michal
authors.initials: M
authors.lastname: Maes
authors.forename: Eran
authors.initials: E
authors.lastname: Hadas
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: David J
authors.initials: DJ
authors.lastname: Volsky
authors.forename: Abraham
authors.initials: A
authors.lastname: Loyter
authors.forename: Assaf
authors.initials: A
authors.lastname: Friedler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D014157:Transcription Factors / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C548807:LEDGF peptide (361-370), human; C504649:PSIP1 protein, human; D010446:Peptide Fragments; D014157:Transcription Factors; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1