13th International HIV Drug Resistance Workshop 8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain

BACKGROUND: The rapid emergence of drug-resistant strains of HIV is a major issue in HIV/AIDS treatment. New viral inhibitors with distinct structural properties are urgently needed to address this problem. Our approach has been to synthesize a series of protease inhibitors (PIs) based on an L-lysine scaffold. The cross-resistance profile of one selected compound, PL- 100, was determined using a selected series of 14 HIV isolates with known reduced susceptibility to other PIs.

METHODS: A series of L-lysine derivatives was first evaluated using recombinant HIV protease enzymatic assays and then in cell culture antiviral assays using wild-type HIV-1 (NL4-3) grown in MT4 cells. One of the most active compounds of the series, PL-100, was further characterized. Activity against a panel of 14 multi-PI-resistant strains was evaluated using the PhenoSense assay (ViroLogic). For comparison, saquinavir, indinavir, nelfinavir, amprenavir and lopinavir were tested in parallel.

RESULTS: PL-100 inhibited HIV protease with a Ki of less than 100 pM, and was highly specific for this particular aspartic protease. The compound inhibited wildtype HIV with an EC₅₀ of 8 nM, while cytotoxicity (CC₅₀) in MT4 cells was 34 µM. In the panel of resistant viruses, there was broad cross-resistance among the approved PIs tested, with a range in median foldchange (FC) of 8.2-fold to 54-fold for the different PIs. In comparison, PL-100 had a median FC of 4.5-fold. Between 11 and 13 isolates had >2.5-fold reduced susceptibility to one of the five approved PIs, and four to 11 isolates had FC >10-fold. In comparison, nine isolates had FC >2.5 and two isolates had >10-fold reduced susceptibility to PL-100. In six of the 14 isolates, the FC for PL-100 was the lowest of the PIs tested, compared to two for APV, three for IDV, two for SQV, and one for LPV. Linear regression between PL- 100 and the approved PIs revealed a weak correlation with amprenavir (r²=0.51) and lopinavir (r²=0.49).

CONCLUSIONS: PL-100 has potent anti-protease and antiviral activity against wild-type HIV-1, and has a favourable cross-resistance profile as compared to the PIs tested in this study.

PRESENTING AUTHOR: G Sévigny

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2004-06-08
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