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Small Molecule Inhibitors of Anthrax Toxin–induced Cytotoxicity Targeted Against Protective Antigen
Author(s) -
Rubert Pérez Charles,
LópezPérez Daneli,
Chmielewski Jean,
Lipton Mark
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01285.x
Subject(s) - anthrax toxin , cytotoxicity , toxin , chemistry , bacillus anthracis , small molecule , antigen , microbiology and biotechnology , biochemistry , biology , in vitro , immunology , bacteria , gene , fusion protein , genetics , recombinant dna
Two molecular scaffolds were designed using the CAVEAT molecular design package to inhibit the oligomerization of protective antigen (PA 63 ), a key protein component of anthrax toxin. The inhibitors were designed to prevent heptamerization of PA 63 by mimicking key residues of PA 63 needed for the intermolecular interactions that stabilize the heptamer. Using the scaffolds identified by CAVEAT, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxin–induced cytotoxicity, with three of the agents demonstrating modest inhibition in murine J774A.1 macrophage cells.