title: Structural determinants for HIV-1 integrase inhibition by beta-diketo acids.
abstract: Among all the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead in anti-HIV-1 integrase drug design. These derivatives inhibit the integration reaction in vitro with a strong specificity for the 3'-end joining step. They are also antiviral and inhibit integration in vivo. The aim of the present study has been to investigate the molecular interactions between DKAs and HIV-1 integrase. We have compared 5CITEP with one of the most potent DKAs reported by the Merck group (L-708,906) and found that 5CITEP inhibits 3'-processing at concentrations where L-708,906 is only active on strand transfer. We also report a novel bifunctional DKA derivative that inhibits 3'-processing even more effectively than 5CITEP. The interactions of these inhibitors with the viral DNA donor ends have been studied by performing experiments with oligonucleotides containing defined modifications. We propose that the bifunctional DKA derivative binds to both the acceptor and donor sites of HIV-1 integrase, whereas the monofunctional L-708,906 derivative binds selectively to the acceptor site.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI/National Institutes of Health, Bethesda, MD 20892-4255, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Xuechun
authors.initials: X
authors.lastname: Zhang
authors.forename: Godwin C G
authors.initials: GC
authors.lastname: Pais
authors.forename: Kiriana
authors.initials: K
authors.lastname: Cowansage
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000090:Acetoacetates / Q000494:pharmacology*; D001483:Base Sequence; D004279:DNA, Viral / Q000737:chemistry; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C400757:1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)propenone; D000090:Acetoacetates; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D007211:Indoles; C403887:L 708906; D013777:Tetrazoles; D019427:HIV Integrase