Mechanism and action characteristics studies of a quinoxalinone compound against HIV-1 replication

This study is to investigate the mechanism and action characteristics of 6-chloro-3-methyl-4-(2- methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1H)-one (XU07011) against HIV-1 replication.  XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses’ infectious assay.  Time of addition was used to test HIV-1 reverse transcription process.  RNA- dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method.  Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics.  The results showed that XU07011 inhibited HIV-1 replication with IC₅₀ of (0.057 ± 0.01) μmol·L⁻¹ which was comparable to nevirapine IC₅₀: (0.046 ± 0.01) μmol·L⁻¹.  Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC₅₀ of (1.1 ± 0.3) µmol·L⁻¹.  The compound showed no effect on RNase H activity.  XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains.  This study could provide a theoretical basis for novel anti-HIV reagents development.