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- Title
Identification of small molecule inhibitors of anthrax lethal factor.
- Authors
Panchal, Rekha G.; Hermone, Ann R.; Tam Luong Nguyen; Tiang Yian Wong, Ann R.; Schwarzenbacher, Robert; Schmidt, James; Lane, Douglas; McGrath, Connor; Turk, Benjamin E.; Burnett, James; Aman, M. Javad; Little, Stephen; Sausville, Edward A.; Zaharevitz, Daniel W.; Cantley, Lewis C.; Liddington, Robert C.; Gussio, Rick; Bavari, Sina
- 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.
- Subjects
METALLOPROTEINASES; BACILLUS anthracis; CHEMICAL inhibitors; ANTHRAX; ZINC; MOLECULAR biology
- Publication
Nature Structural & Molecular Biology, 2004, Vol 11, Issue 1, p67
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb711