Abstract
The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have Ki values in the 0.5–5 μM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.
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Acknowledgements
This research was sponsored by the Medical Biological Defense Research Program, US Army Medical Research and Materiel Command, project no. 0242C012. We acknowledge the US National Cancer Institute for the allocation of computing time and staff support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center. We thank the staff of the Stanford Synchrotron Radiation Laboratory (SSRL) for assistance during data collection. We also thank S. Leppla (US National Institutes of Health (NIH)) and D. Hsu for the LF protein preparation used in the crystal structure. Portions of this research were carried out at the SSRL, a national user facility operated by Stanford University on behalf of the US Department of Energy (DOE), Office of Basic Energy Sciences (BES). The SSRL Structural Molecular Biology Program is supported by the DOE, Office of Biological and Environmental Research, and by the NIH, National Center for Research Resources, Biomedical Technology Program, and the National Institute of General Medical Sciences.
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Panchal, R., Hermone, A., Nguyen, T. et al. Identification of small molecule inhibitors of anthrax lethal factor. Nat Struct Mol Biol 11, 67–72 (2004). https://doi.org/10.1038/nsmb711
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DOI: https://doi.org/10.1038/nsmb711
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