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. 2002 Oct;46(10):3292-7.
doi: 10.1128/aac.46.10.3292-3297.2002.

Inhibition of Human Immunodeficiency Virus Type 1 Integration by Diketo Derivatives

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Free PMC article

Inhibition of Human Immunodeficiency Virus Type 1 Integration by Diketo Derivatives

Wim Pluymers et al. Antimicrob Agents Chemother. .
Free PMC article

Abstract

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.

Figures

FIG. 1.
FIG. 1.
Chemical structures of the diketo derivatives.
FIG. 2.
FIG. 2.
Combination experiments. Shown are isobologram representations of the combined inhibitory effects of L-708,906 and the protease inhibitor nelfinavir (upper panel), the nucleoside reverse transcriptase inhibitor zidovudine (middle panel), and the nonnucleoside reverse transcriptase inhibitor nevirapine (lower panel) on the cytopathic effect of HIV-1(IIIB) in MT-4 cells. Lines represent the unity lines for fractional inhibitory concentration (FIC) equal to 1 and 0.5, respectively.
FIG. 3.
FIG. 3.
Time-of-addition experiment. MT-4 cells were infected with HIV-1(IIIB) at a multiplicity of infection of 0.5, and the test compounds were added at different times postinfection. Viral p24 Ag production was determined at 31 h postinfection and is expressed as the log10 of the p24 Ag content in picograms per milliliter. Symbols: •, control; ▴, dextran sulfate (20 μM); formula image, AZT (1.9 μM); ▪, ritonavir (2.8 μM); *, L-708,906 (173 μM).
FIG. 4.
FIG. 4.
Analysis of HIV integration by quantitative PCR. 293T cells were transduced with HIV-1 vectors at a multiplicity of infection of 10 in the absence (▾) or in the presence of 750 nM AZT (▪) or 25 μM L-708,906 (♦). At different time points after infection, DNA extracts were prepared and analyzed by real-time PCR. Late reverse transcripts (A) were quantified, as well as 2-LTR circles (B) and integrated proviral DNA (C). A no-amplification control was run in parallel (•). The graph represents a typical experiment.

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