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IDX12899 anti-HIV-1 activity and resistance profile is superior to efavirenz
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Reported by Jules Levin
16th Intl HIV Drug Resistance Workshop, June 12-16, 2007, Barbados
J Jakubik, M Seifer, L Gray, C Chapron, A Patty,
C Dousson and DN Standring
Idenix Pharmaceuticals Inc., Cambridge, MA, USA
BACKGROUND: The phospho-heterocyclic NNRTI, IDX12899, is a potent and selective inhibitor of HIV-1 replication in tissue culture. Here we describe the resistance profile of IDX12899 in vitro, using WT and NNRTI-resistant HIV-1, and the in vitro interactions of IDX12899 with other anti-HIV agents. Results of X-ray co-crystallization studies are also presented.
METHODS: Enzyme and cell-based assays were conducted with all known WT HIV genotypes, 40 HIV-1 clinical isolates possessing the most prevalent single, double and triple NNRTI resistance mutations, and virus strains exhibiting high (>200-fold) resistance to efavirenz. Viral breakthrough studies and selection of drug-resistant isolates were conducted in cell culture systems. The impact of PI, NRTI or FI agents on the activity of IDX12899 was tested at two fixed doses in media supplemented with 45% human serum. For structural studies, recombinant HIV-1 K103N/Y181C RT protein was concentrated in the presence of IDX12899 and crystallized in successive micro-seeding experiments.
RESULTS: IDX12899 showed nM to sub-nM activity against a broad panel of subtype B and non-B WT HIV-1 isolates, with 50% cellular cytotoxicity observed at 15 to 70 _M. Potency was retained against panels of clinical isolates containing various single and double NNRTI mutations, including those associated with high-level resistance to efavirenz (L100I, K103N, K103N/Y181C, Y188C, G190S). Breakthrough studies in MT-2 cells demonstrated slower development of resistance to IDX12899 (45 days) than to efavirenz (17 days). Resistance mutations selected with IDX12899 (E138K and 138K/Y181I at passages 4 and 16, respectively) differed from those selected with efavirenz (G190A and V179D/G190A at passages 4 and 10, respectively). Combination studies suggest enhanced activity for IDX12899 combined with approved HIV-1 medications, and revealed no negative interactions. X-ray co-crystallization established the 3-D structure of IDX12899 complexed with HIV-1 RT K103N/Y181C.
CONCLUSIONS: IDX12899 demonstrated potent antiviral activity in vitro, a higher genetic barrier to resistance compared to efavirenz, and enhanced activity in combination with other approved drugs, suggesting that IDX12899 is a promising second-generation NNRTI development candidate. Clinical evaluation of IDX12899 has been initiated.
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