title: [Mechanism and action characteristics studies of a quinoxalinone compound against HIV-1 replication].
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.
authors.affiliation: 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.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Ba
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Cao
authors.forename: Bai-Ling
authors.initials: BL
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D019829:Nevirapine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D016914:Ribonuclease H / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D011810:Quinoxalines; D013876:Thiophenes; C000604302:XU07011; D019829:Nevirapine; D012194:RNA-Directed DNA Polymerase; D016914:Ribonuclease H