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

Figures & data

Figure 1. Structures of representative ALLINIs. Chemotypes of each ALLNI are highlighted in red colour.

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. Structures and dose–response curves of confirmed positives 1–3. Data represent the mean ± SD of three independent experiments.

Table 1. Reported hit rates for the screening of libraries drugs

Target	Acronym	Hit rate (%)	Screened library (size)		No. of hits	Reference
Insulin-degrading enzyme	IDE	0.45	APTEEUS-Universite de Lille Library	1120	5	Leroux et al.^42
Human 3-hydroxy-3-methyl-glutaryl-coenzyme A	HMG-CoA reductase	3.3	NIH Clinical Collections librarie	727	24	Bessoff et al.^43
Aspergillus fumigatus chitinase A1	AfChiA1	0.08	Dundee Drug Discovery Unit diversity	59904	48	Lockhart et al.^44
Dengue virus non-structural proteins NS3 and NS interaction	NS3/NS5	1.6	2P2I-Oriented Chemical Library	1664	26	Milhas et al.^45
HIV virus Nef and Hck kinase interaction	Nef/SH3-Hck	0.2	2P2I-Oriented Chemical Library	1664	2	Milhas et al.^45
HIV virus integrase and LEDGF/p75 IBD domain	IN/IBD	0.17	Protein kinase inhibitor library, REDOX library	578	1	This paper

Table 2. Inhibitory potencies of confirmed positives

Compound	Name	IC50 (µM)
1	Ebselen	7.70
2	Curcumin	14.52
3	p38 MAP kinase inhibitor IV	116.90

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.

Table 3. Activity of ebselen on targets from pathogen.

Target	IC50（µM）	Covalent	Reference
Cryptosporidium parvum glucose-6-phosphate isomerase	8.33	Yes	Eltahan et al.^46
Tumor marker endothelial 8 and protective antigen interaction	1.7	Yes	Cryan et al.^37
Trypanosoma brucei hexokinase 1	0.05	Yes	Gordhan et al.^47
Escherichia coli thioredoxin reductase	0.52 (Ki)	Yes	Lu et al.^48
C-terminal domain of HIV-1 capsid	0.047	Yes	Thenin-Houssier et al.^39
Bacillus anthracis thioredoxin reductase	1	ND	Gustafsson et al.^49
Clostridium difficile cysteine protease domain	0.0069	Yes	Bender et al.^50
New Delhi metallo-β-lactamase	0.38	Yes	Chiou et al.^51
Mycobacterium tuberculosis antigen 85	0.063	Yes	Favrot et al.^52
Hepatitis C Virus NS3 Helicase-Nucleic Acid interaction	1.1/0.9	Yes	Mukherjee et al.^53
Cryptosporidium parvum Inosine 5′-monophosphate dehydrogenase	0.71	Yes	Sarwono et al.^54
Pseudomonas aeruginosa Diguanylate Cyclases	5	Yes	Lieberman et al.^55

Figure 5. Ability of other thiol-modifying agents to inhibit LEDGF/p75 IBD-IN interaction.

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