ABSTRACT:
HIV-1 reverse transcriptase inhibitors (RTIs) are a integral part of current antiretroviral therapeutic regimens. However, owing to the in vivo selection of resistant HIV-1 variants that exhibit varying levels of cross-resistance, there remains a pressing need for new RTIs. AG1549 (formerly known as S-1153) is a novel HIV-1 non-nucleoside RTI (NNRTI) that exhibits potent in vitro antiviral activity against laboratory strains and clinical isolates, as well as RT-resistant variants with EC50 values ranging from 2.2 to 10.3 nM and EC90 values ranging from 6.0 to 21/5 nM. The antiviral activity of AG1549 has also been evaluated against a panel of recombinant virus strains generated from clinical isolates that contain RT amino acid substitutions known to confer resistance to other NNRTIs and RTIs. No significant reductions in susceptibility to AG1549 W were observed for recombinant virus strains containing the K103N, V106A, or L100I substitutions. Potent antiviral activity was also exhibited against recombinant strains that contained multiple NNRTI substitutions, including L100I/K103N or K103N/P225H. Previous results have described the isolation of two resistant HIV-1IIB variants with V106A/%227L or K103T/V106A/L234I genotypes after greater than nine serial passages in the presence of increasing concentrations of AG1549. Additional serial passage studies using different HIV laboratory strains including NNRTI resistant strains have also been initiated in MT-2 cells. In addition, DNA sequence analysis of plasma HIV RNA obtained from patients enrolled in Phase I/II AG1549 clinical trials is underway. The potent in vitro antiviral activity and resistance profile for AG1549 demonstrate its potential usefulness as a key component in antiretroviral therapeutic regimens.
