Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
Center for Food and Drug Evaluation & Inspection of Henan, Zhengzhou, China.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):906-912. doi: 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.
HIV-1 整合酶（IN）上的 Lens-epithelium-derived growth-factor (LEDGF/p75)-结合位点是抗病毒化学疗法的一个有吸引力的靶点。与该位点结合的小分子化合物被称为 LEDGF-IN 抑制剂（LEDGINs）。在这项研究中，筛选了化合物文库以鉴定 LEDGF/p75-IN 相互作用的新抑制剂。Ebselen（2-苯基-1,2-苯并异硒唑-3-酮）是一种报道的抗 HIV-1 药物，被鉴定为 LEDGF/p75-IN 相互作用的中等微摩尔抑制剂。Ebselen 通过与 LEDGF/p75 结合来抑制相互作用，并且 DTT（二硫苏糖醇）可以逆转 ebselen 抑制相互作用的能力。BLI 实验表明，ebselen 可能与 LEDGF/p75 中的还原硫醇形成硒-硫键。据我们所知，我们首次表明，小分子化合物 ebselen 通过直接与 LEDGF/p75 结合来抑制 LEDGF/p75-IN 相互作用。这里发现的化合物可用作探针化合物来设计和开发新的 LEDGF/p75-IN 相互作用破坏剂。
