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

BACKGROUND: A majority of drug-experienced patients in North America harbour HIV that is resistant to one or more FDA-approved antiretroviral agents. Recent studies suggest that the effectiveness of salvage therapies that include lopinavir/ritonavir and amprenavir/ritonavir regimens may be diminished for patients with more than 6–7 PI mutations at baseline. The epidemiological increase of MDR HIV strains poses a challenge to the development of new antiretroviral agents targeted to mutant protease and reverse transcriptase enzymes. There is an urgent need for potent and broad-spectrum PIs that be used to treat MDR HIV strains and to prevent the development of MDR HIV in primary treatment settings.

METHODS: We have implemented a structure-based approach for the design of novel HIV protease inhibitors (PIs) with high potency against WT and MDR viruses and evaluated their activity against WT and MDR mutant forms of HIV PR in enzyme-based assay and cell-based antiviral assays.

RESULTS: We have designed and synthesized a series of HIV-1 PR inhibitors (SPI inhibitors) that interact with a conserved substructure of the enzyme’s active site that is relatively unaffected by mutations known to cause HIV PI drug resistance. In a cell-based antiviral assay, five SPI inhibitors exhibited an average IC₅₀ value for WT HXB2 HIV of 6.6 nM (range: 4.5–10 nM). More importantly, SPI inhibitors retained potency against a panel of seven recombinant HIV-1 viruses derived from MDR patient clinical isolates containing 10–17 mutations in PR region. The average IC₅₀ value against these mutants was 15.7 nM (range: 7.6–24 nM). For comparison, seven FDA-approved HIV PIs, APV, IDV, LPV, RTV, NFV, SQV and ATV have an average IC₅₀ value for WT of 31 nM (3.5–70 nM) and an average IC₅₀ value against mutants of more than 2100 nM (range: 159 to >5440 nM). All SPI inhibitors have CC₅₀ values in MT4 cells more than 10000 nM, which corresponds to a selectivity index of >1000.

CONCLUSIONS: SPI inhibitors are highly active against WT and MDR HIV isolates, and have the potential for further development.

PRESENTING AUTHOR: SV Gulnik

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2004-06-08
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