Structure–activity relationship studies of a novel series of anthrax lethal factor inhibitors

Johnson, Sherida L.; Chen, Li-Hsing; Barile, Elisa; Emdadi, Aras; Sabet, Mojgan; Yuan, Hongbin; Wei, Jun; Guiney, Donald G.; Pellecchia, Maurizio

doi:10.1016/j.bmc.2009.03.040

Cited by 21 publications

(18 citation statements)

References 30 publications

(34 reference statements)

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“…Other groups have screened chemical libraries with a variety of read-outs for the in vitro proteolytic activity of LF (Panchal et al, 2004;Lee et al, 2004;Min et al, 2004;Forino et al, 2005;Fridman et al, 2005;Kocer et al, 2005;Johnson et al, 2007Johnson et al, , 2009. A phenylfuran-2-ylmethylenerhodanineacetic acid derivative (B1-11B3) showed a good inhibition constant in vitro (K i = 32 nM) and gave a synergistic protection with ciprofloxacin in an anthrax mouse model (Forino et al, 2005).…”

Section: Inhibitorsmentioning

confidence: 99%

The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity

Tonello

Montecucco

2009

Molecular Aspects of Medicine

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Section: Inhibitorsmentioning

confidence: 99%

The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity

Tonello

Montecucco

2009

Molecular Aspects of Medicine

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“…To further analyze the efficacy of compound 22 in cell, we confirmed its ability of protecting macrophages from LF/PA induced cell death (31, 39), and in preventing MEK1 cleavage in Hela cells (Fig. 3d) (40).…”

Section: Resultsmentioning

confidence: 82%

Targeting Metalloproteins by Fragment‐Based Lead Discovery

et al. 2011

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It has been estimated that nearly one third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases or many others in which the metal ion is either of catalytic or structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal binding pharmacophores in the current screening libraries. Herein we describe a novel fragment based drug discovery approach using a metal targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics.

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“…Several inhibitors of the enzymatic and pathogenic activity of LF have been identifi ed. [16][17][18] In order to identify inhibitors of LF a variety of approaches has been utilized, such as library screenings, Mass Spectroscopy-based mining and scaffold-based NMR searches. [ 17,19,20 ] Results from these screenings have yielded a variety of novel small molecules that inhibit LF at low micromolar concentrations.…”

Section: A Magnetic Nanosensor-based Methods Is Described To Screen a mentioning

confidence: 99%

Identification of Toxin Inhibitors Using a Magnetic Nanosensor‐Based Assay

Santiesteban

Kaittanis

Perez

2013

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A magnetic nanosensor-based method is described to screen a library of drugs for potential binding to toxins. Screening is performed by measuring changes in the magnetic relaxation signal of the nanosensors (bMR nanosensors) in aqueous suspension upon addition of the toxin. The Anthrax lethal factor (ALF) is selected as a model toxin to test the ability of our bMR nanosensor-based screening method to identify potential inhibitors of the toxin. Out of 30 molecules screened, sulindac, naproxen and fusaric acid are found to bind LF, with dissociation constants in the low micromolar range. Further biological analysis of the free molecules in solution indicate that sulindac and its metabolic products inhibited LF cytotoxicity to macrophages with IC50 values in the micromolar range. Meanwhile, fusaric acid is found to be less effective at inhibiting LF cytotoxicity, while naproxen does not inhibit LF toxicity. Most importantly, when the sulindac and fusaric acid-bMR nanosensors themselves are tested as LF inhibitors, as opposed to the corresponding free molecules, they are stronger inhibitors of LF with IC50 values in the nanomolar range. Taken together, these studies show that a bMR nanosensors-based assay can be used to screen known drugs and other small molecules for inhibitor of toxins. The method can be easily modified to screen for inhibitors of other molecular interactions and not only the selected free molecule can be study as potential inhibitors but also the bMR nanosensors themselves achieving greater inhibitory potential.

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Structure–activity relationship studies of a novel series of anthrax lethal factor inhibitors

Cited by 21 publications

References 30 publications

The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity

The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity

Targeting Metalloproteins by Fragment‐Based Lead Discovery

Identification of Toxin Inhibitors Using a Magnetic Nanosensor‐Based Assay

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