title: HIV-1 integrase: the next target for AIDS therapy?
abstract: HIV-1 is the aetiological agent of AIDS. Present treatment of AIDS uses a combination therapy with reverse transcriptase and protease inhibitors. Recently, the integrase (IN), the third enzyme of HIV-1 which is necessary for the integration process of proviral DNA into the host genome, has reached as a legitimate new drug target. Several families of inhibitors of the catalytic core domain of HIV-1 IN exhibiting submicromolar activities have now been identified. Our contribution in this field was related to the development of new polyhydroxylated styrylquinolines. The latter compounds have proved to be potent HIV-1 IN inhibitors, that block the replication of HIV-1 in cell culture, and are devoid of cytotoxicity. The crystal structure of the catalytically active core domain of a HIV-1 IN mutant has been determined. The active site region is identified by the position of two of the conserved carboxylate residues essential for catalysis, Asp64 and Asp116, which coordinate a Mg2+ ion, whereas the third catalytic residue, Glu152 does not participate in metal binding. However, a recent molecular dynamics simulation of the HIV-1 IN catalytic domain provides support to the hypothesis that a second metal ion is likely to be carried into the HIV-1 IN active site by the DNA substrate. The structure of a complex of the HIV-1 IN core domain with the inhibitor 5-CITEP has been recently reported. The inhibitor binds centrally in the active site of the IN and makes a number of close contacts with the protein, particularly with Lys156, Lys159 and Gln148, amino acids which were identified to be near the active site of the enzyme, through site-directed mutagenis and photo-crosslinking experiments. The exact mechanism by which HIV-1 IN inhibitors block the catalytic activity of the protein remains unknown. However, several putative pharmacophore components have been characterized. All these groups lie in a possible coordination to a divalent ion, supporting thus the hypothesis that the interaction causing the inhibition is mediated by one or two cations. Finally, among the HIV-1 IN inhibitors, three classes have proved to exhibit significant antiviral activities. Thus, it seems likely that the efficient use of HIV-1 IN as a target for rational design will become possible in the next future, possibly through the use of combination regimens including IN inhibitors.
authors.affiliation: Unité associée au CNRS, faculté de pharmacie, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. jean.dangelo@cep.u-psud.fr
authors.forename: J
authors.initials: J
authors.lastname: d'Angelo
authors.forename: J F
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: D
authors.initials: D
authors.lastname: Desmaële
authors.forename: F
authors.initials: F
authors.lastname: Zouhiri
authors.forename: H
authors.initials: H
authors.lastname: Leh
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D015394:Molecular Structure; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D016662:Virus Integration / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D011804:Quinolines; D011994:Recombinant Proteins; D019427:HIV Integrase