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Title: Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor

Abstract

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1237749
Resource Type:
Journal Article
Resource Relation:
Journal Name: FEBS Letters; Journal Volume: 589; Journal Issue: 24PartB
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Maize, Kimberly M., Kurbanov, Elbek K., Johnson, Rodney L., Amin, Elizabeth Ambrose, and Finzel, Barry C.. Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor. United States: N. p., 2016. Web. doi:10.1016/j.febslet.2015.11.005.
Maize, Kimberly M., Kurbanov, Elbek K., Johnson, Rodney L., Amin, Elizabeth Ambrose, & Finzel, Barry C.. Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor. United States. doi:10.1016/j.febslet.2015.11.005.
Maize, Kimberly M., Kurbanov, Elbek K., Johnson, Rodney L., Amin, Elizabeth Ambrose, and Finzel, Barry C.. Tue . "Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor". United States. doi:10.1016/j.febslet.2015.11.005.
@article{osti_1237749,
title = {Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor},
author = {Maize, Kimberly M. and Kurbanov, Elbek K. and Johnson, Rodney L. and Amin, Elizabeth Ambrose and Finzel, Barry C.},
abstractNote = {The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.},
doi = {10.1016/j.febslet.2015.11.005},
journal = {FEBS Letters},
number = 24PartB,
volume = 589,
place = {United States},
year = {Tue Jul 05 00:00:00 EDT 2016},
month = {Tue Jul 05 00:00:00 EDT 2016}
}
  • We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor activity of protease-activated anthrax toxins were evaluated. • All anthrax toxin variants exhibited potent systemic anti-tumor activity in mice. • A dual MMP/uPA-activated anthrax toxin displayed a superior safety profile. • Clinical development of a dual MMP/uPA-activated anthrax toxin is feasible.« less
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  • No abstract prepared.