title: Biotinylated biphenyl ketone-containing 2,4-dioxobutanoic acids designed as HIV-1 integrase photoaffinity ligands.
abstract: The diketo acid (DKA) class of HIV-1 integrase inhibitors are thought to function by chelating divalent metal ions within the enzyme catalytic center. However, differences in mutations conferring resistance among sub-families of DKA inhibitors suggest that multiple binding orientations may exist. In order to facilitate identification of DKA-binding sites, biotin-tagged biphenyl ketone-containing 2,4-dioxobutanoic acids were prepared as DKA photoaffinity probes. Introduction of biotin was obtained by means of Huisgen [3+2] cycloaddition 'click chemistry.' Two photoprobes, 5a and 5b, were prepared bearing short and long linker segments, respectively, between the biotin and DKA nucleus. The greatest inhibitory potency was shown by 5b, which inhibited 3'-processing and strand transfer reactions with IC50 values of > 333 microM and 12.4 microM, respectively. In cross-linking assays designed to measure disruption of substrate DNA binding, the photoprobes behaved similarly to a reference DKA inhibitor. Analogues 5a and 5b represent novel photoaffinity ligands, which may be useful in clarifying the HIV-1 binding interactions of DKA inhibitors.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Zhao
authors.forename: Elena A
authors.initials: EA
authors.lastname: Semenova
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.forename: Marc
authors.initials: M
authors.lastname: Nicklaus
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000090:Acetoacetates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D019921:Biotinylation; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D019920:Photoaffinity Labels / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000090:Acetoacetates; D019380:Anti-HIV Agents; D001713:Biphenyl Compounds; D003432:Cross-Linking Reagents; D019428:HIV Integrase Inhibitors; D008024:Ligands; D019920:Photoaffinity Labels; C016635:acetoacetic acid; D019427:HIV Integrase