Quantitative high-throughput screening identifies inhibitors of anthrax-induced cell death |
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Authors: | Ping Jun Zhu John P Hobson Noel Southall Cunping Qiu Craig J Thomas Jiamo Lu James Inglese Wei Zheng Stephen H Leppla Thomas H Bugge Christopher P Austin Shihui Liu |
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Institution: | 1. NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States;2. Proteases and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, United States;3. Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Bethesda, MD 20892, United States |
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Abstract: | Here, we report the results of a quantitative high-throughput screen (qHTS) measuring the endocytosis and translocation of a β-lactamase-fused-lethal factor and the identification of small molecules capable of obstructing the process of anthrax toxin internalization. Several small molecules protect RAW264.7 macrophages and CHO cells from anthrax lethal toxin and protected cells from an LF-Pseudomonas exotoxin fusion protein and diphtheria toxin. Further efforts demonstrated that these compounds impaired the PA heptamer pre-pore to pore conversion in cells expressing the CMG2 receptor, but not the related TEM8 receptor, indicating that these compounds likely interfere with toxin internalization. |
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