Synthesis and Biological Evaluation of Geminal Disulfones as HIV-1 Integrase Inhibitors

Abstract

Integration of HIV-1 viral DNA into the host genome is carried out by HIV-integrase (IN) and is a critical step in viral replication. Although several classes of compounds have been reported to inhibit IN in enzymatic assays, inhibition is not always correlated with antiviral activity. Moreover, potent antiviral IN inhibitors such as the chicoric acids do not act upon the intended enzymatic target but behave as entry inhibitors instead. The charged nature of the chicoric acids contributes to poor cellular uptake, and these compounds are further plagued by rapid ester hydrolysis in vivo. To address these critical deficiencies, we designed neutral, nonhydrolyzable analogues of the chicoric acids. Herein, we report the synthesis, enzyme inhibition studies, and cellular antiviral data for a series of geminal disulfones. Of the 10 compounds evaluated, 8 showed moderate to high inhibition of IN in purified enzyme assays. The purified enzyme data correlated with antiviral assays for all but two compounds, suggesting alternative modes of inhibition. Time-of-addition studies were performed on these analogues, and the results indicate that they inhibit an early stage in the replication process, perhaps entry. In contrast, the most potent member of the correlative group shows behavior consistent with IN being the cellular target.

Direct Inactivation of Human Immunodeficiency Virus Type 1 by a Novel Small-Molecule Entry Inhibitor, DCM205

“…There is a great need for small-molecule inhibitors that are widely effective against all subtypes of HIV and that are cost-effective. We previously identified a potent and selective inhibitor of HIV-1, DCM205, that inhibits the activity of the purified HIV-1 integrase but that appears to exert antiviral activity at an entry step, based on time-of-addition studies (25). The results of the studies reported here demonstrate that this novel small-molecule inhibitor directly inactivates HIV-1 in the absence of a cellular target.…”

“…Having established that DCM205 (previously referred to as compound 6 [25]) exerts its antiviral activity early in the viral replication process, we used SPR to determine whether the compound would directly bind to the HIV-1 envelope glycoprotein. For these experiments a well-characterized soluble trimeric oligomerized envelope glycoprotein, ogp140 (29), was used.…”

“…1A), is a potent and selective inhibitor of HIV-1 NL4-3 and that it blocks an early stage of the replication cycle (25). Herein, we report on the ability of DCM205 to tightly bind to gp120 and to directly inactivate HIV-1 infectivity.…”

“…The procedures for the FIA (10,15,25) and the HIV-1 p24 antigen-capture ELISA (16) were described previously. Both assays were used to monitor virus replication in cell cultures and to quantify the susceptibilities of HIV-1 and SIV to antiviral drugs.…”

“…The cells were incubated for 4 days at 37°C in a humidified 5% CO 2 atmosphere. The cells were fixed and immunostained by previously described methods (25,26). Data were plotted as a percentage of the control foci (no drug) versus the inhibitor concentration.…”