[Efficient synthetic inhibitors of anthrax lethal factor]
Published online before print June 27, 2005
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502733102
OPEN ACCESS ARTICLE
Biochemistry
Efficient synthetic inhibitors of anthrax lethal factor
( NMR | protective antigen | fragment-based design | metalloprotease | drug design )
Martino Forino *, Sherida Johnson *, Thiang Y. Wong *, Dmitri V. Rozanov *, Alexei Y. Savinov *, Wei Li *, Roberto Fattorusso *, Barbara Becattini *, Andrew J. Orry , Dawoon Jung *, Ruben A. Abagyan , Jeffrey W. Smith *, Ken Alibek ¶, Robert C. Liddington *, Alex Y. Strongin *, and Maurizio Pellecchia *||
*Burnham Institute, Cancer Research Center and Infectious and Inflammatory Disease Center, 10901 North Torrey Pines Road, La Jolla, CA 92037; The Scripps Research Institute, Molecular Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037; National Center for Biodefense, George Mason University, 10900 University Boulevard, PWII Building, Room 160, MSN 1A8, Manassas, VA 20110; and ¶Advanced Biosystems, 5904 Richmond Highway, Suite 300, Alexandria, VA 22303
Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 23, 2005 (received for review April 3, 2005)
Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.<<
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