Abstract
Anthrax is caused by infection with Bacillus anthracis, a spore forming, rod-shaped, encapsulated gram positive bacteria. The disease manifests itself in distinct ways depending on the route of entry of infective bacterial spores: cutaneous, inhalational, and gastrointestinal. Though rare in humans, inhalational anthrax has become a major concern due to the capacity for spores to be weaponized. The limited success of antibiotic therapy has motivated investigation of complementary therapeutic strategies that target the bacterias secreted toxin. The zinc-dependent metalloproteinase lethal factor (LF) is a critical component of anthrax toxin and an important potential target for small molecule drugs. In the past few years, a number of approaches have been taken to identify LF inhibitors, from generating conventional metal chelating substrate analogs to random screening of diverse compound libraries. These efforts have produced several different classes of specific nanomolar range inhibitors. Some compounds have fared well in animal models for anthrax toxemia and infection, and these inhibitors and their derivatives may form the basis for future therapies to treat the disease in humans.
Keywords: Anthrax, proteases, metalloenzymes, protease inhibitors, drug discovery, bacterial toxins
Current Pharmaceutical Biotechnology
Title: Discovery and Development of Anthrax Lethal Factor Metalloproteinase Inhibitors
Volume: 9 Issue: 1
Author(s): Benjamin E. Turk
Affiliation:
Keywords: Anthrax, proteases, metalloenzymes, protease inhibitors, drug discovery, bacterial toxins
Abstract: Anthrax is caused by infection with Bacillus anthracis, a spore forming, rod-shaped, encapsulated gram positive bacteria. The disease manifests itself in distinct ways depending on the route of entry of infective bacterial spores: cutaneous, inhalational, and gastrointestinal. Though rare in humans, inhalational anthrax has become a major concern due to the capacity for spores to be weaponized. The limited success of antibiotic therapy has motivated investigation of complementary therapeutic strategies that target the bacterias secreted toxin. The zinc-dependent metalloproteinase lethal factor (LF) is a critical component of anthrax toxin and an important potential target for small molecule drugs. In the past few years, a number of approaches have been taken to identify LF inhibitors, from generating conventional metal chelating substrate analogs to random screening of diverse compound libraries. These efforts have produced several different classes of specific nanomolar range inhibitors. Some compounds have fared well in animal models for anthrax toxemia and infection, and these inhibitors and their derivatives may form the basis for future therapies to treat the disease in humans.
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Cite this article as:
Turk E. Benjamin, Discovery and Development of Anthrax Lethal Factor Metalloproteinase Inhibitors, Current Pharmaceutical Biotechnology 2008; 9 (1) . https://dx.doi.org/10.2174/138920108783497604
DOI https://dx.doi.org/10.2174/138920108783497604 |
Print ISSN 1389-2010 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4316 |
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