Identification of Small Molecules That Inhibit the Interaction of TEM8 with Anthrax Protective Antigen Using a FRET Assay

Cryan, Lorna M.; Habeshian, Kaiane; Caldwell, Thomas P.; Morris, Meredith T.; Ackroyd, P. Christine; Christensen, Kenneth A.; Rogers, Michael S.

doi:10.1177/1087057113478655

Cited by 19 publications

(16 citation statements)

References 33 publications

(87 reference statements)

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“…However, ebselen seems to be a promiscuous compound. Data from PubChem reveals that ebselen was found to be active in 193 out of 1023 drug screenings, with 126 of these hits coming from confirmatory screens 37 . And the promiscuity of ebselen may be partly attributed to its known ability of modifying cysteine residues.…”

Section: Resultsmentioning

confidence: 99%

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

Zhang

Yan

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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2020) The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 906-912, 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. ARTICLE HISTORY

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Section: Resultsmentioning

confidence: 99%

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

Zhang

Yan

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Recently, antibodies against the capsule have been shown to have a protective effect in various challenge models, but this would also depend on early treatment (38, 130,223). Additional therapeutics targeting PA and its action include receptor decoys (225,231,247), polyvalent competitive peptides (14), and small molecules that inhibit receptor-toxin interaction (50). Inhibitors that act on the PA translocation function include dominant negative mutant PA proteins (28, 229), small-molecule oligomerization inhibitors (195,268), β-cyclodextrin-based blockers of the PA oligomer channel (114), and other pore-blocking agents (for a review see 180).…”

Section: Therapeuticsmentioning

confidence: 98%

Anthrax Pathogenesis

Moayeri

Leppla

Vrentas

et al. 2015

Annu. Rev. Microbiol.

235

213

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Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

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“…The most protective peptide improved survival in LT-challenged Fisher rats (6 of 6 animals survived with treatment vs 1 of 12 controls). Another group used a fluorescence resonance transfer (FRET) system to screen for compounds that interfered with PA–CMG2 or PA–TEM8 interactions [57,58]. With this technique, cisplatin inhibited both CMG2 and PA while tannic acid interacted with CMG2 alone and ebselen and thimersol inhibited PA and TEM8 interactions.…”

Section: Toxin-directed Therapies For the Management Of B Anthracmentioning

confidence: 99%

An overview of investigational toxin-directed therapies for the adjunctive management ofBacillus anthracisinfection and sepsis

Ohanjanian

Remy

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction Sepsis with Bacillus anthracis infection has a very high mortality rate despite appropriate antibiotic and supportive therapies. Over the past 15 years, recent outbreaks in the US and in Europe, coupled with anthrax's bioterrorism weapon potential, have stimulated efforts to develop adjunctive therapies to improve clinical outcomes. Since lethal toxin and edema toxin (LT and ET) make central contributions to the pathogenesis of B. anthracis, these have been major targets in this effort. Areas covered Here, the authors review different investigative biopharmaceuticals that have been recently identified for their therapeutic potential as inhibitors of LT or ET. Among these inhibitors are two antibody preparations that have been included in the Strategic National Stockpile (SNS) and several more that have reached Phase I testing. Presently, however, many of these candidate agents have only been studied in vitro and very few tested in bacteria-challenged models. Expert opinion Although a large number of drugs have been identified as potential therapeutic inhibitors of LT and ET, in most cases their testing has been limited. The use of the two SNS antibody therapies during a large-scale exposure to B. anthracis will be difficult. Further testing and development of agents with oral bioavailability and relatively long shelf lives should be a focus for future research.

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Identification of Small Molecules That Inhibit the Interaction of TEM8 with Anthrax Protective Antigen Using a FRET Assay

Cited by 19 publications

References 33 publications

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

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

Anthrax Pathogenesis

An overview of investigational toxin-directed therapies for the adjunctive management ofBacillus anthracisinfection and sepsis

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