HIV-1 is the aetiological agent of AIDS. Present treatment of AIDS uses a c
ombination therapy with reverse transcriptase and protease inhibitors. Rece
ntly, 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 a
s a legitimate new drug target. Several families of inhibitors of the catal
ytic core domain of HIV-1 IN exhibiting submicromolar activities have now b
een identified. Our contribution in this field was related to the developme
nt of new polyhydroxylated styrylquinolines. The latter compounds have prov
ed 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 conserv
ed carboxylate residues essential for catalysis, Asp(64) and Asp(116), whic
h coordinate a Mg2+ ion, whereas the third catalytic residue, Glu(152) does
not participate in metal binding. However, a recent molecular dynamics sim
ulation 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 s
ite by the DNA substrate. The structure of a complex of the HIV-1 IN core d
omain 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 co
ntacts 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 e
xact mechanism by which HIV-1 IN inhibitors block the catalytic activity of
the protein remains unknown. However, several putative pharmacophore compo
nents have been characterized. All these groups lie in a possible coordinat
ion to a divalent ion, supporting thus the hypothesis that the interaction
causing the inhibition is mediated by one or two cations. Finally, among th
e HIV-1 IN inhibitors, three classes have proved to exhibit significant ant
iviral 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, p
ossibly through the use of combination regimens including IN inhibitors. (C
) 2001 Editions scientifiques et medicales Elsevier SAS.