Mechanism and action characteristics studies of a quinoxalinone compound against HIV-1 replication.
- Author:
Ming-Yu BA
1
;
Ying-Li CAO
;
Bai-Ling XU
;
Ying GUO
Author Information
1. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
- Publication Type:Journal Article
- MeSH:
Anti-HIV Agents;
chemistry;
pharmacology;
Drug Resistance, Viral;
HEK293 Cells;
HIV-1;
physiology;
Humans;
Inhibitory Concentration 50;
Molecular Structure;
Nevirapine;
pharmacology;
Quinoxalines;
pharmacology;
RNA-Directed DNA Polymerase;
metabolism;
Ribonuclease H;
metabolism;
Thiophenes;
pharmacology;
Virus Replication;
drug effects
- From:
Acta Pharmaceutica Sinica
2013;48(6):860-865
- CountryChina
- Language:Chinese
-
Abstract:
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-(1 H)-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) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x 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.
