HIV-1 integrase:: the next target for AIDS therapy?

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 Mg2+ 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. (C) 2001 Editions scientifiques et medicales Elsevier SAS.