The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75

• Main Authors: Da-Wei Zhang, Hao-Li Yan, Xiao-Shuang Xu, Lei Xu, Zhi-Hui Yin, Shan Chang, Heng Luo
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: allnis; integrase; ledgf/p75-integrase interaction; hiv-1
• Online Access: http://dx.doi.org/10.1080/14756366.2020.1743282

Lens-epithelium-derived growth-factor (LEDGF/p75)-binding site on HIV-1 integrase (IN), is an attractive target for antiviral chemotherapy. Small-molecule compounds binding to this site are referred as LEDGF-IN inhibitors (LEDGINs). In this study, compound libraries were screened to identify new inhibitors of LEDGF/p75-IN interaction. Ebselen (2-phenyl-1,2-benzisoselenazol-3-one), a reported anti-HIV-1 agent, was identified as a moderate micromolar inhibitor of LEDGF/p75-IN interaction. Ebselen inhibited the interaction by binding to LEDGF/p75 and the ability of ebselen to inhibit the interaction could be reversed by dithiothreitol (DTT). BLI experiment showed that ebselen probably formed selenium-sulphur bonds with reduced thiols in LEDGF/p75. To the best of our knowledge, we showed for the first time that small-molecule compound, ebselen inhibited LEDGF/p75-IN interaction by directly binding to LEDGF/p75. The compound discovered here could be used as probe compounds to design and develop new disrupter of LEDGF/p75-IN interaction.