title: The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction.
abstract: From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3'-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
authors.affiliation: School of Chemistry, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. keller@uow.edu.au.
authors.forename: Neal
authors.initials: N
authors.lastname: Dalton
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Boyle
authors.forename: Nicholas
authors.initials: N
authors.lastname: Vandegraaf
authors.forename: John
authors.initials: J
authors.lastname: Deadman
authors.forename: David I
authors.initials: DI
authors.lastname: Rhodes
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coates
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Pyne
authors.forename: Paul A
authors.initials: PA
authors.lastname: Keller
authors.forename: John B
authors.initials: JB
authors.lastname: Bremner
mesh_terms: D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; D014443:Tyrosine; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1