title: Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of photoactivatable diketo acid-containing inhibitors as affinity probes.
abstract: The diketo acid (DKA) class of HIV-1 integrase (IN) inhibitors is thought to function by chelating divalent metal ions on the enzyme catalytic site. However, differences in mutations conferring resistance to various DKA inhibitors suggest that multiple binding orientations may exist. In order to facilitate identification of DKA binding sites, a series of photoactivable analogues of two potent DKAs was prepared as novel photoaffinity probes. In cross-linking assays designed to measure disruption of substrate DNA binding, the photoprobes behaved similarly to a reference DKA inhibitor. Molecular modeling studies suggest that such photoprobes interact within the IN active site in a manner similar to that of the parent DKAs. Analogues Ia-c are novel photoaffinity ligands useful in clarifying the HIV-1 binding interactions of DKA inhibitors.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. mario.sechi@uniss.it
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Luciano
authors.initials: L
authors.lastname: Sannia
authors.forename: Roberto
authors.initials: R
authors.lastname: Dallocchio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dessì
authors.forename: Rasha I
authors.initials: RI
authors.lastname: Al-Safi
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D003432:Cross-Linking Reagents; D019428:HIV Integrase Inhibitors; D017319:Photosensitizing Agents; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1