Title

Identification Of Toxin Inhibitors Using A Magnetic Nanosensor-Based Assay

Keywords

anthrax; drug repurposing; iron oxide; magnetic nanosensors; toxins

Abstract

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 IC 50 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 IC 50 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. Magnetic (bMR) nanosensors are used to screen a library of small molecules for binding to and inhibition of the Anthrax lethal factor (LF). Out of 30 different bMR nanosensors, only two, containing sulindac and fusaric acid on their surfaces, were able to inhibit the protease activity of LF. Meanwhile, the sulindac bMR nanosensor by itself was a potent inhibitor of LF macrophage cytoxocity with an IC50 in the low nanomolar range. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Publication Date

3-26-2014

Publication Title

Small

Volume

10

Issue

6

Number of Pages

1202-1211

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1002/smll.201301824

Socpus ID

84896929098 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84896929098

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