Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor

Catherine H. Schein, Deliang Chen, Lili Ma, John J. Kanalas, Jian Gao, Maria Estrella Jimenez, Laurie E. Sower, Mary A. Walter, Scott R. Gilbertson, Johnny Peterson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.

Original languageEnglish (US)
Pages (from-to)1288-1300
Number of pages13
JournalToxins
Volume4
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Adenosine Triphosphate
Enterotoxigenic Escherichia coli
Bacillus anthracis
Bordetella pertussis
Anthrax
Vibrio cholerae
Pathogens
Bacilli
Substrates
Infection
Phosphoric Monoester Hydrolases
Adenylyl Cyclases
Escherichia coli
Libraries
Disease Outbreaks
Diarrhea
Bacteria
Animals
Nucleotides
Animal Models

Keywords

  • Adenylyl cyclase toxin
  • Computational design
  • Fluorenone
  • Library screening

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Schein, C. H., Chen, D., Ma, L., Kanalas, J. J., Gao, J., Jimenez, M. E., ... Peterson, J. (2012). Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. Toxins, 4(11), 1288-1300. https://doi.org/10.3390/toxins4111288

Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. / Schein, Catherine H.; Chen, Deliang; Ma, Lili; Kanalas, John J.; Gao, Jian; Jimenez, Maria Estrella; Sower, Laurie E.; Walter, Mary A.; Gilbertson, Scott R.; Peterson, Johnny.

In: Toxins, Vol. 4, No. 11, 11.2012, p. 1288-1300.

Research output: Contribution to journalArticle

Schein, CH, Chen, D, Ma, L, Kanalas, JJ, Gao, J, Jimenez, ME, Sower, LE, Walter, MA, Gilbertson, SR & Peterson, J 2012, 'Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor', Toxins, vol. 4, no. 11, pp. 1288-1300. https://doi.org/10.3390/toxins4111288
Schein CH, Chen D, Ma L, Kanalas JJ, Gao J, Jimenez ME et al. Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. Toxins. 2012 Nov;4(11):1288-1300. https://doi.org/10.3390/toxins4111288
Schein, Catherine H. ; Chen, Deliang ; Ma, Lili ; Kanalas, John J. ; Gao, Jian ; Jimenez, Maria Estrella ; Sower, Laurie E. ; Walter, Mary A. ; Gilbertson, Scott R. ; Peterson, Johnny. / Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. In: Toxins. 2012 ; Vol. 4, No. 11. pp. 1288-1300.
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