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Antiviral activity of SPI-256 against WT and MDR Strains
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Reported by Jules Levin
15th Intl HIV Drug Resistance Workshop, June 13-17, 2006, Sitges, Spain
"...SPI-256 is highly active against wild-type & multi-drug resistant-HIV proteases.... it is superior in activity to all approved HIV PIs... In cell-based assays, SPI-256 demonstrated potent antiviral activity... retained low nanomolar potency (<30 nM) against a select panel of 7 highly PI resistant MDR strains... SPI-256 has the potential to be used as part of first line as well as salvage therapy."
SV Gulnik1, E Alfonina1, MEissenstat1, H Yokoe1, B Yu1, M Markowitz2, NT Parkin3 and JW Erickson1
1Sequoia Pharmaceuticals, Inc, Gaithersburg, MD, USA
2Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY, USA
3Monogram Biosciences, Inc, San Francisco, CA, USA
BACKGROUND: SPI-256 is an HIV protease (HIV PR) inhibitor designed using structure-based approaches to be potent against wild-type (WT) and multi-drug-resistant (MDR) HIV PR. Investigators report here the evaluation of SPI-256's in vitro activity using enzymatic and different cell-based antiviral assays.
METHODS: The enzyme inhibition was characterized using recobimant WT and MDR HIV PRs and flourogenic substrate. Antiviral activity was evaluated in cell-based assays in PBMC & MT4 cells. The PhenoSense HIV assay (Monogram Biosciences) was used to evaluate the antiviral activity of SPI-256 against a panel of highly PI-resistant MDR HIV strains.
RESULTS
SPI-256 is highly active against purified WT & MDR-HIV proteases with Ki in the piocmolar range; it is superior in activity to all approved HIV PIs, including lopinavir & atazanavir. In cell-based assays, SPI-256 demonstrated potent antiviral activity against sub-type B & non-B HIV primary isolates, and against viruses with different co-receptor tropism, with IC50 values = 2 nM. SPI-256 retained low nanomolar potency (<30 nM) against a select panel of 7 highly PI resistant MDR strains derived from clinical isolates in MT4 cells.
In the PhenoSense assay, SPI-256 exhibited an average IC50 value of 0.3 nM (range: 0.2-0.4 nM) against viruses lacking known PI resistance mutations, and was 4-50 fold more potent than FDA-apprioved PIs (IC50 1.2-16.3 nM).
Among isolates with >50-fold resistance to reference PIs (range: >252 to >2,925 nM) and/or 6 primary PI mutations (n=12), the average SPI-256 IC50 was 12.9 nM (range: 1.8-34 nM). SPI-256 exhibited an IC50 of 85 nM in PBMC against a dual-tropic, primary MDR-HIV strain that was recently isolated from a patient with rapid progression to AIDS, which contained 12 mutations in PR accompanied by p7/p1 gag cleavage site mutations.
CONCLUSION: SPI-256 is more potent than currently approved PIs against WT HIV-1 in different in vitro assays. It maintains nanomolar potency against worst-case scenario MDR HIV isolates and is equipotent against viruses of different clades & co-receptor tropism. SPI-256 has the potential to be used as part of first line as well as salvage therapy in treatment regimens worldwide.
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