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. 2020 Dec;35(1):906-912.
doi: 10.1080/14756366.2020.1743282.

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

Da-Wei Zhang  1 , Hao-Li Yan  2 , Xiao-Shuang Xu  1 , Lei Xu  1 , Zhi-Hui Yin  3 , Shan Chang  1 , Heng Luo  4
Affiliations

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

Da-Wei Zhang et al. J Enzyme Inhib Med Chem. 2020 Dec.

Abstract

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.

Keywords: ALLNIs; HIV-1; LEDGF/p75-integrase interaction; integrase.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Structures of representative ALLINIs. Chemotypes of each ALLNI are highlighted in red colour.
Figure 2.
Figure 2.
Overview and primary screening results. (A) Screening cascade. (B) Z-factor frequency distribution for 12 screening plates. (C) Replicate plot from screening 578 compounds for disruption of LEDGF/p75 IBD-IN interaction at 50 µM. The red dash line indicates our cut-off point of 70% inhibition and 5 compounds inhibited the interaction by more than 70%.
Figure 3.
Figure 3.
Structures and dose–response curves of confirmed positives 1–3. Data represent the mean ± SD of three independent experiments.
Figure 4.
Figure 4.
Determination of the inhibition mode of ebselen on LEDGF/p75-IN interaction. (A) The inhibition of ebselen on LEDGF/p75-IN interaction was abolished in the presence of 50 µM DTT. (B) Ebselen inhibited the LEDGF/p75-IN interaction by binding to LEDGF/p75. (C) Association/dissociation kinetics of ebselen for LEDGF/p75 determined by Octet. (D) Time-dependent inhibition of the LEDGF/p75-IN interaction with ebselen. The data are representative of results obtained in three independent experiments. Each point is carried out in triplicate; error bars show the mean ± SD.
Figure 5.
Figure 5.
Ability of other thiol-modifying agents to inhibit LEDGF/p75 IBD-IN interaction.
See this image and copyright information in PMC

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