Inhibition of human immunodeficiency virus type 1 integration by diketo derivatives

A series of diketo derivatives was found to inhibit human immunodeficiency virus type 1 (HIV-1) integrase activity. Only L-708,906 inhibited the replication of HIV-1(III(B)) (50% effective concentration, 12 micro M), HIV-1 clinical strains, HIV-1 strains resistant to Reverse Transcriptase or fusion inhibitors, HIV-2 (ROD strain) and simian immunodeficiency virus (MAC(251)). The combinations of L-708,906 with zidovudine, nevirapine, or nelfinavir proved to be subsynergistic. In Cell Culture, addition of L-708,906 could be postponed for 7 h after Infection, a moment coinciding with HIV integration. Inhibition of integration in Cell Culture was confirmed by quantitative Alu-PCR.