Svarovskaia ES, Zhang X, Pais GC, Marchand C, Pommier Y, Burke TR, Pathak VK; HIV DRP Symposium Antiviral Drug Resistance.

Program Abstr HIV DRP Symp Antivir Drug Resist. 2001 Dec 9-12; 2: Abstract no. 12.

HIV Drug Resistance Program, NCI at Frederick, Frederick, MD 21702

Previous studies have shown that 3-Aryl-1,3-diketo acid derivatives are potent inhibitors of HIV-1 integrase and HIV-1 replication (Hazuda et al., Science 287:646-650, 2000). In an effort to identify novel and 3-Aryl-1,3-diketo acid derivatives that exhibit potent inhibition of HIV-1 replication, a series of derivatives were synthesized and tested for their ability to inhibit the 3' processing and strand transfer reactions catalyzed in vitro with purified HIV-1 integrase. Compounds that exhibited 50% inhibitory concentrations (IC(50)) of less than 10:M were selected for further antiviral testing. A single cycle replication assay was used to evaluate antiviral activity. An envelope deficient HIV-1 based retroviral vector containing the firefly luciferase reporter gene was psuedotyped with vesicular stomatitis virus G glycoprotein (VSV-G) and the ability of the compounds to inhibit viral replication was measured by determining the amount of luciferase activity in the infected cells. Among the compounds tested, two compounds containing azide groups significantly inhibited HIV-1 replication and reduced luciferase expression to 5 and 15% of the activity detected in untreated controls. A structurally related compound lacking the azide groups did not show antiviral activity, indicating the importance of the azide group in viral inhibition. The antiviral activities of these compounds were further verified by determination of the concentrations needed to inhibit viral replication by 50% (IC(50)). The IC(50) values for these compounds were 1-10:M range, which were comparable to the previously reported IC(50) for 3-Aryl-1,3-diketo acid derivative L708, 906. Additionally, these compounds inhibited replication competent HIV-1 in a dose-dependant manner. The cytotoxicity (CC(50)) of the azide group containing compounds was determined to be in the range of 60-400:M, indicating a therapeutic index greater than 100. These results strongly suggest that azide group containing 3-Aryl-1,3-diketo acid derivatives are potent inhibitors of HIV-1 integrase activity and viral replication.

Publication Types:

• Meeting Abstracts

Keywords:

• Acids
• Antiviral Agents
• Azides
• HIV Integrase
• HIV-1
• In Vitro
• Keto Acids
• antagonists & inhibitors

Other ID:

• GWAIDS0012080

UI: 102249578

From Meeting Abstracts