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Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor
Sealy Center for Structural Biology and Molecular Biophysics, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
Sealy Center for Vaccine Development, Center for Biodefense and Emerging Infections, University of Texas Medical Branch, Galveston, TX 77555, USA
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Member, Institute for Translational Studies, and Faculty, Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
Department of Chemistry, University of Houston, Houston, TX 77004, USA
Mission Pharmacal Company, San Antonio, TX 78230, USA
Chrysalis Biotherapeutics, Galveston, TX 77555, USA
* Author to whom correspondence should be addressed.
Received: 24 September 2012; in revised form: 25 October 2012 / Accepted: 1 November 2012 / Published: 8 November 2012
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.
Keywords: computational design; library screening; fluorenone; adenylyl cyclase toxin
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MDPI and ACS Style
Schein, C.H.; Chen, D.; Ma, L.; Kanalas, J.J.; Gao, J.; Jimenez, M.E.; Sower, L.E.; Walter, M.A.; Gilbertson, S.R.; Peterson, J.W. Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor. Toxins 2012, 4, 1288-1300.
Schein CH, Chen D, Ma L, Kanalas JJ, Gao J, Jimenez ME, Sower LE, Walter MA, Gilbertson SR, Peterson JW. Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor. Toxins. 2012; 4(11):1288-1300.
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 W. 2012. "Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor." Toxins 4, no. 11: 1288-1300.