17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

SMALL-MOLECULE INHIBITORS OF HIV-1 INTEGRASE

Antivir Ther. 2008; 13(Suppl. 3):A18 (abstract no. 16)

JJ Wu, G Milot, F Beaulieu, J-E Bouchard, Y Xiao, S Dandache, K Gouveia, A Forte, S Garde, Z Wang, M Ge, T Oudanonh and BR Stranix
Ambrilia Biopharma Inc., Montreal, Canada

BACKGROUND: HIV-1 integrase has recently been validated clinically as an important target for the treatment of HIV/AIDS. Raltegravir is the first marketed integrase inhibitor and there are also a number of integrase inhibitors in clinical trials. Here, we report novel compounds as integrase inhibitors.

METHODS: In single-cycle infection assays, MT4 cells were infected with a defective envelope (env-), luciferase-bearing NL-4.3 virus pseudotyped with HIV-1 env (HXBc2) or VSV-G env. In multicycle infection assays, the antiviral activity of the compounds was determined by a cytoprotection assay (MTT) using NL-4.3 in MT4 cells. The cytotoxicity of the compounds was tested in parallel using the same assay but without adding virus to the cells. The time-of-addition experiments were performed in MT4 cells infected with virus pseudotpyed with HXBc2 env in single-cycle infection assays. The drug was added to the culture at the concentration of EC₉₅ at different time intervals.

RESULTS: We reported previously some vitamin B6 derivatives as non-cytotoxic integrase inhibitors with activities against integrase enzyme and wild-type HIV-1 viruses in cellular assays. These derivatives displayed a different mechanism of action of integrase strand transfer inhibition by potentially binding to a novel site on integrase. A recent lead optimization effort has led to the discovery of new vitamin B6 derivatives, which show improved activities against integrase enzyme and viruses. These new derivatives demonstrate selectivity toward integrase enzyme over other enzymes (that is, >150-fold more specific for integrase versus reverse transcriptase). In the cell-based assays, these compounds display not only potent antiviral activity (EC₅₀ <100 nM) but also selectivity against cellular integrase. A similar antiviral activity was observed when HIV-1 envelope was replaced with VSV-G suggesting that these compounds are post-entry inhibitors. Furthermore, the time-of-addition studies indicate that these compounds have a very similar inhibitory profile to that of raltegravir.

CONCLUSIONS: A novel series of vitamin B6-based integrase inhibitors has been developed. These compounds demonstrate potent inhibition against HIV-1 integrase strand transfer activity, antiviral activity and specificity against HIV-1 integrase in cellular assays.

2008-06-10
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