Structure-based redesign of an edema toxin inhibitor

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3′,5′-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15 μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria.

Original languageEnglish (US)
Pages (from-to)368-376
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2012

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National Institute of Allergy and Infectious Diseases (U.S.)
Adenylyl Cyclases
Cyclic AMP
Edema
Bacteria
Lead compounds
Derivatives
Enterotoxigenic Escherichia coli
Anthrax
Benzoic Acid
Bioassay
Macrophages
Bacilli
Structure-Activity Relationship
Biological Assay
Solubility
Escherichia coli
Monocytes
Cultured Cells
Diarrhea

Keywords

  • Adenylyl cyclase toxin inhibitor
  • Anthrax
  • Cell-based assay
  • Computer aided design
  • ETEC (enterotoxigenic E. coli)
  • Non-nucleotide inhibitors
  • Toxicity profiling

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Chen, D., Ma, L., Kanalas, J. J., Gao, J., Pawlik, J., Jimenez, M. E., ... Schein, C. H. (2012). Structure-based redesign of an edema toxin inhibitor. Bioorganic and Medicinal Chemistry, 20(1), 368-376. https://doi.org/10.1016/j.bmc.2011.10.091

Structure-based redesign of an edema toxin inhibitor. / Chen, Deliang; Ma, Lili; Kanalas, John J.; Gao, Jian; Pawlik, Jennifer; Jimenez, Maria Estrella; Walter, Mary A.; Peterson, Johnny; Gilbertson, Scott R.; Schein, Catherine H.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 1, 01.01.2012, p. 368-376.

Research output: Contribution to journalArticle

Chen, D, Ma, L, Kanalas, JJ, Gao, J, Pawlik, J, Jimenez, ME, Walter, MA, Peterson, J, Gilbertson, SR & Schein, CH 2012, 'Structure-based redesign of an edema toxin inhibitor', Bioorganic and Medicinal Chemistry, vol. 20, no. 1, pp. 368-376. https://doi.org/10.1016/j.bmc.2011.10.091
Chen D, Ma L, Kanalas JJ, Gao J, Pawlik J, Jimenez ME et al. Structure-based redesign of an edema toxin inhibitor. Bioorganic and Medicinal Chemistry. 2012 Jan 1;20(1):368-376. https://doi.org/10.1016/j.bmc.2011.10.091
Chen, Deliang ; Ma, Lili ; Kanalas, John J. ; Gao, Jian ; Pawlik, Jennifer ; Jimenez, Maria Estrella ; Walter, Mary A. ; Peterson, Johnny ; Gilbertson, Scott R. ; Schein, Catherine H. / Structure-based redesign of an edema toxin inhibitor. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 1. pp. 368-376.
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