HYDROXYLATED AROMATIC INHIBITORS OF HIV-1 INTEGRASE

Efficient replication of HIV-1 requires integration of a DNA copy of t he viral genome into a chromosome of the host cell. Integration is cat alyzed by the viral integrase, and we have previously reported that ph enolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAFE, 2), and curcumin confer inhibitory activity against HIV-1 integrase. We now extend these findings by performing a comprehensive structure-activity relationship using CAPE analogues. Approximately 3 0 compounds have been prepared as HIV integrase inhibitors based on th e structural lead provided by CAPE, which has previously been shown to exhibit an IC50 value of 7 mu M in our integration assay. These analo gues were designed to examine specific features of the parent CAFE str ucture which may be important for activity. Among the features examine d for their effects on inhibitory potency were ring substitution, side chain length and composition, and phenyl ring conformational orientat ion. In an assay which measured the combined effect of two sequential steps, dinucleotide cleavage and strand transfer, several analogues ha ve IC50 values for 3'-processing and strand transfer lower than those of CAFE. Inhibition of strand transfer was assayed using both blunt-en ded and ''precleaved'' DNA substrates. Disintegration using an integra se mutant lacking the N-terminal zinc finger and C-terminal DNA-bindin g domains was also inhibited by these analogues, suggesting that the b inding site for these compounds resides in the central catalytic core. Several CAFE analogues were also tested for selective activity agains t transformed cells. Taken together, these results suggest that the de velopment of novel antiviral agents for the treatment of acquired immu ne deficiency syndrome can be based upon inhibition of HIV-1 integrase .