XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications


Seville, Spain, 2–5 July 2002


AZIDE GROUP CONTAINING 3-ARYL-1, 3-DIKETO ACID DERIVATIVES ARE POTENT INHIBITORS OF HIV-1 REPLICATION

Antivir Ther. 2002;7(Suppl 1):S13 (abstract no. 15)

ES Svarovskaia1, R Barr1, X Zhang2, GCG Pais2, C Marchand3, Y Pommier3, TR Burke Jr2 and VK Pathak1
1HIV Drug Resistance Program, NCI at Frederick, Frederick, Md., USA; 2Laboratory of Medicinal Chemistry, NCI at Frederick, Frederick, Md., USA; and 3Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, Md., USA

BACKGROUND: Previous studies have shown that diketo acid derivatives are potent inhibitors of HIV-1 integrase and HIV-1 replication (Hazuda et al., Science. 2000 Jan 28;287(5453):646-50). The goal of the project was to identify novel diketo acid derivatives that inhibit HIV-1 replication and to characterize their in vitro and in vivo antiviral activity.

METHODS: A series of derivatives were synthesized and tested for their ability to inhibit the 3' processing and strand transfer reactions in vitro and viral replication in vivo. The ability of the compounds to inhibit 3' processing and strand transfer activities was determined in in vitro assays. Their ability to inhibit HIV-1 replication was measured in a single cycle as well as a multi-round assay. The structure of viral DNA 2-LTR circle junctions was determined in the presence and absence of the compounds by quantitative real-time PCR and DNA sequencing.

RESULTS: Among the compounds tested, two compounds containing azide groups significantly inhibited HIV-1 replication in both single round and multiple round assays. The therapeutic indices of the compounds (IC50 7–13 µM; CC50 60–600 µM) were similar to L708,906. We also constructed integrase mutants T66I and T66I/S153Y that were previously shown to be resistant to L708,906 compound (Hazuda et al., Science. 2000 Jan 28;287(5453):646-50). These mutants were resistant to the azide group containing diketo acid derivatives, indicating that these derivatives inhibit HIV-1 replication at the level of integration. In addition, amounts of 2-LTR circles in the presence of azide group containing diketo acid derivatives were shown to be elevated in comparison to untreated control during HIV-1 infection. The 2-LTR circle junctions present in cells infected in the absence and presence of the compounds were characterized by DNA sequencing.

CONCLUSION: These results indicate that diketo acid derivatives containing azide groups are potent inhibitors of HIV-1 integrase and viral replication.

PRESENTING AUTHOR: VK Pathak

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2002-07-02
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