title: Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site.
abstract: An optimised method of solution cyclisation gave us access to a series of peptides including SLKIDNLD (2). We investigated the crystallographic complexes of the HIV integrase (HIV-IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding site, including hydrogen bonds with residues Thr125 and Gln95, that have not previously been described as being accessible within the binding site. We show that the peptides inhibit the interaction of lens epithelium-derived growth factor (LEDGF) with HIV-IN in a proximity AlphaScreen assay and in an assay for the LEDGF enhancement of HIV-IN strand transfer. The interactions identified represent a potential framework for the development of new HIV-IN inhibitors.
authors.affiliation: Avexa Ltd, 576 Swan Street, Melbourne 3121, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Rhodes
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.forename: Nick
authors.initials: N
authors.lastname: Vandegraaff
authors.forename: Dharshini
authors.initials: D
authors.lastname: Jeevarajah
authors.forename: Janet
authors.initials: J
authors.lastname: Newman
authors.forename: John
authors.initials: J
authors.lastname: Martyn
authors.forename: Jonathan A V
authors.initials: JA
authors.lastname: Coates
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Ede
authors.forename: Philip
authors.initials: P
authors.lastname: Rea
authors.forename: John J
authors.initials: JJ
authors.lastname: Deadman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D010456:Peptides, Cyclic; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1