Low Molecular Weight Inhibitors of the Protease Anthrax Lethal Factor

Δάλκας, Γεώργιος; Papakyriakou, Athanasios; Vlamis-Gardikas, Alexios; Spyroulias, Georgios A.

doi:10.2174/138955708783744083

Cited by 11 publications

(4 citation statements)

References 47 publications

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“…Types of small-molecule inhibitors of LF activity, both competitive and noncompetitive and each with numerous candidate agents, have been reported on and reviewed [121-123]. These inhibitors have included hydroxymates, zinc-metallo-proteases, amino-glycosides, quinolone urea derivatives, heterocyclic zinc chelators, drug structure scaffolds, hydrazones, several natural products (e.g., catechins), host defensins, compounds with polyphenol motifs and phenylfuran, phenylpyrazole and phenylpyrrole carboxylic derivatives [121].…”

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

confidence: 99%

“…These inhibitors have included hydroxymates, zinc-metallo-proteases, amino-glycosides, quinolone urea derivatives, heterocyclic zinc chelators, drug structure scaffolds, hydrazones, several natural products (e.g., catechins), host defensins, compounds with polyphenol motifs and phenylfuran, phenylpyrazole and phenylpyrrole carboxylic derivatives [121]. Very few of these agents have been studied in in vivo models though, making their potential clinical application unclear.…”

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

confidence: 99%

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

confidence: 99%

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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“…Since the discovery of one of the first LF inhibitors in 2002 (62), numerous research efforts to search for the “ideal” (126) LF inhibitor were undertaken. Because of the great number of these studies, which are reviewed elsewhere (7, 127-129), the examples below are not exhaustive and rather serve the specific scope of the current review. While LF and EF inhibitors can act at any appropriate stage of the toxin’s pathway, for instance by preventing LF/EF interaction with PA, most of the designed compounds perform intracellularly by inhibiting the metalloprotease activity of LF or the adenylase cyclase activity of EF.…”

Section: Pa Lf and Ef As Antitoxin Design Targetsmentioning

confidence: 99%

Designing inhibitors of anthrax toxin

Nestorovich

Bezrukov

2014

Expert Opinion on Drug Discovery

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Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination.

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“…The metalloproteinase LF has been the subject of numerous drug design efforts, reviewed by Dalkas (2008) [117], Turk (2008) [118], Tonello (2009) [119], and Bouzianas (2010) [4]. Hydroxymates, aminoglycosides, and natural products in the catechin family have all been shown to be promising LF inhibitors with sub-micromolar K i or IC 50 values [118] (Fig.…”

Section: Current Research Directionsmentioning

confidence: 99%

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

Beierlein

Anderson²

2011

CMC

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Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics.

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Low Molecular Weight Inhibitors of the Protease Anthrax Lethal Factor

Cited by 11 publications

References 47 publications

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

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

Designing inhibitors of anthrax toxin

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

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