Efficient synthetic inhibitors of anthrax lethal factor

doi:10.1073/pnas.0502733102

Efficient synthetic inhibitors of anthrax lethal factor

^*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 (received for review April 3, 2005)

Abstract

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.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: mpellecchia{at}burnham.org.
↵ † M.F. and S.J. contributed equally to this work.
Author contributions: R.C.L., A. Y. Strongin, and M.P. designed research; M.F., S.J., T.Y.W., D.V.R., A. Y. Savinov, W.L., R.F., J.W.S., K.A., R.C.L., A. Y. Strongin, and M.P. performed research; M.F., S.J., T.Y.W., D.V.R., A. Y. Savinov, W.L., R.F., A.J.O., D.J., R.A.A., R.C.L., A. Y. Strongin, and M.P. analyzed data; S.J., B.B., and M.P. contributed new reagents/analytic tools; and M.P. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: LF, lethal factor; PA, protective antigen; MAPKK, mitogen-activated protein kinase kinase; MMP, metalloproteinase.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 1ZXV).
Freely available online through the PNAS open access option.