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, Asp 64 and Asp 116, which coordinate a Mg 2+ ion, whereas the third catalytic residue, Glu 152 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 Lys 156, Lys 159 and Gln 148, 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.