title: Inhibition of HIV-1 integrase dimerization and activity with crosslinked interfacial peptides.
abstract: Alternative modes of inhibition for the design of anti-HIV therapies are sought due to the resistance of HIV to a number of the currently approved drugs. A non-active site strategy for generating potent inhibitors of HIV-1 integrase is described based on blocking protein association. Peptides α5 and α6 derived from the HIV-1 integrase dimeric interface have previously demonstrated efficacious dimerization inhibition of HIV-1 integrase. Due to the proximity of the termini of these peptides within the integrase structure, a focused library of tethered agents was designed based on crosslinking the peptides α5 and α6 to mimic a larger interfacial region. The best crosslinked inhibitors are approximately five-fold more potent against HIV-1 integrase than the individual peptides alone or in combination. The most active agents have an inhibitory constant in the mid-nM range and function via a dissociative mechanism of inhibition.
authors.affiliation: Department of Chemistry, 560 Oval Drive, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
mesh_terms: D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D010455:Peptides; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1